Purine derivatives as purinergic receptor antagonists

ABSTRACT

Use of a compound of formula (I) wherein R 1  is selected from alkyl, aryl, alkoxy, aryloxy, 0thioalkyl, thioaryl, CN, halo, NR 5 R 6 , NR 4 COR 5 , NR 4 CONR 5 R 6 , NR 4 CO 2 R 7  and NR 4 SO 2 R 7 ; R 2  is selected from N, O or S-containing heteroaryl groups, wherein the heteroaryl group is attached via an unsaturated carbon atom which is adjacent to one or two N, O or S-heteroatom(s), other than ortho, ortho-disubstituted heteroaryl groups; R 3  is selected from H, alkyl, COR 8 , CONR 9 R 10 , CONR 8 NR 9 R 10 , CO 2 R 11  and SO 2 R 11 ; R 4 , R 5  and R 6  are independently selected from H, alkyl and aryl or where R 5  and R 6  are in an (NR 5 R 6 ) group then R 5  and R 6  may be linked to form a heterocyclic ring; R 7  is selected from alkyl and aryl; R 8 , R 9  and R 10  are independently selected from H, alkyl and aryl, or R 9  and R 10  may be linked to form a heterocyclic ring, or where R 8 , R 9  and R 10  are in a (CONR 8 NR 9 R 10 ) group, R 8  and R 9  may be linked to form a heterocyclic group; and R 1  is selected from alkyl and aryl, or a pharmaceutically acceptable salt thereof or prodrug thereof, in the treatment or prevention of a disorder in which the blocking of purine receptors, particularly adenosine receptors and more particularly A 2A  receptors, may be beneficial, particularly wherein said disorder is a movement disorder such as Parkinson&#39;s disease or said disorder is depression, cognitive or memory impairment, acute or chronic pain, ADHD or narcolepsy, or for neuroprotection in a subject; compounds of formula (I) for use in therapy; and novel compounds of formula (I) per se.

The present invention relates to purine derivatives and their use in therapy. In particular, the present invention relates to the treatment of disorders in which the reduction of purinergic neurotransmission could be beneficial. The invention relates in particular to blockade of adenosine receptors and particularly adenosine A_(2A) receptors, and to the treatment of movement disorders such as Parkinson's disease.

Movement disorders constitute a serious health problem, especially amongst the elderly sector of the population. These movement disorders are often the result of brain lesions. Disorders involving the basal ganglia which result in movement disorders include Parkinson's disease, Huntington's chorea and Wilson's disease. Furthermore, dyskinesias often arise as sequelae of cerebral ischaemia and other neurological disorders.

There are four classic symptoms of Parkinson's disease: tremor, rigidity, akinesia and postural changes. The disease is also commonly associated with depression, dementia and overall cognitive decline. Parkinson's disease has a prevalence of 1 per 1,000 of the total population. The incidence increases to 1 per 100 for those aged over 60 years. Degeneration of dopaminergic neurones in the substantia nigra and the subsequent reductions in interstitial concentrations of dopamine in the striatum are critical to the development of Parkinson's disease. Some 80% of cells from the substantia nigra need to be destroyed before the clinical symptoms of Parkinson's disease are manifested.

Current strategies for the treatment of Parkinson's disease are based on transmitter replacement therapy (L-dihydroxyphenylacetic acid (L-DOPA)), inhibition of monoamine oxidase (e.g. Deprenyl®), dopamine receptor agonists (e.g. bromocriptine and apomorphine) and anticholinergics (e.g. benztrophine, orphenadrine). Transmitter replacement therapy in particular does not provide consistent clinical benefit, especially after prolonged treatment when “on-off” symptoms develop, and this treatment has also been associated with involuntary movements of athetosis and chorea, nausea and vomiting. Additionally current therapies do not treat the underlying neurodegenerative disorder resulting in a continuing cognitive decline in patients. Despite new drug approvals, there is still a medical need in terms of improved therapies for movement disorders, especially Parkinson's disease. In particular, effective treatments requiring less frequent dosing, effective treatments which are associated with less severe side-effects, and effective treatments which control or reverse the underlying neurodegenerative disorder, are required.

Blockade of A₂ adenosine receptors has recently been implicated in the treatment of movement disorders such as Parkinson's disease (Richardson, P. J. et al., Trends Pharmacol. Sci. 1997, 18, 338-344) and in the treatment of cerebral ischaemia (Gao, Y. and Phillis, J. W., Life Sci. 1994, 55, 61-65). The potential utility of adenosine A_(2A) receptor antagonists in the treatment of movement disorders such as Parkinson's Disease has recently been reviewed (Mally, J. and Stone, T. W., CNS Drugs, 1998, 10, 311-320).

Adenosine is a naturally occurring purine nucleoside which has a wide variety of well-documented regulatory functions and physiological effects. The central nervous system (CNS) effects of this endogenous nucleoside have attracted particular attention in drug discovery, owing to the therapeutic potential of purinergic agents in CNS disorders (Jacobson, K. A. et al., J. Med. Chem. 1992, 35, 407-422). This therapeutic potential has resulted in considerable recent research endeavour within the field of adenosine receptor agonists and antagonists (Bhagwhat, S. S.; Williams, M. Exp. Opin. Ther. Patents 1995, 5, 547-558).

Adenosine receptors represent a subclass (P₁) of the group of purine nucleotide and nucleoside receptors known as purinoreceptors. The main pharmacologically distinct adenosine receptor subtypes are known as A₁, A_(2A), A_(2B) (of high and low affinity) and A₃ (Fredholm, B. B., et al., Pharmacol. Rev. 1994, 46, 143-156). The adenosine receptors are present in the CNS (Fredholm, B. B., News Physiol. Sci., 1995, 10, 122-128).

The design of P₁ receptor-mediated agents has been reviewed (Jacobson, K. A., Suzuki, F., Drug Dev. Res., 1997, 39, 289-300; Baraldi, P. G. et al., Curr. Med. Chem. 1995, 2, 707-722), and such compounds are claimed to be useful in the treatment of cerebral ischemia or neurodegenerative disorders, such as Parkinson's disease (Williams, M. and Burnstock, G. Purinergic Approaches Exp. Ther. (1997), 3-26. Editor: Jacobson, Kenneth A.; Jarvis, Michael F. Publisher: Wiley-Liss, New York, N.Y.)

It has been speculated that xanthine derivatives such as caffeine may offer a form of treatment for attention-deficit hyperactivity disorder (ADHD). A number of studies have demonstrated a beneficial effect of caffeine on controlling the symptoms of ADHD (Garfinkel, B. D. et al., Psychiatry, 1981, 26, 395-401). Antagonism of adenosine receptors is thought to account for the majority of the behavioural effects of caffeine in humans and thus blockade of adenosine A_(2A) receptors may account for the observed effects of caffeine in ADHD patients. Therefore a selective A_(2A) receptor antagonist may provide an effective treatment for ADHD but without the unwanted side-effects associated with current therapy.

Adenosine receptors have been recognised to play an important role in regulation of sleep patterns, and indeed adenosine antagonists such as caffeine exert potent stimulant effects and can be used to prolong wakefulness (Porkka-Heiskanen, T. et al., Science, 1997, 276, 1265-1268). Recent evidence suggests that a substantial part of the actions of adenosine in regulating sleep is mediated through the adenosine A_(2A) receptor (Satoh, S., et al., Proc. Natl. Acad. Sci., USA, 1996). Thus, a selective A_(2A) receptor antagonist may be of benefit in counteracting excessive sleepiness in sleep disorders such as hypersomnia or narcolepsy.

It has recently been observed that patients with major depression demonstrate a blunted response to adenosine agonist-induced stimulation in platelets, suggesting that a dysregulation of A_(2A) receptor function may occur during depression (Berk, M. et al, 2001, Eur. Neuropsychopharmacol. 11, 183-186). Experimental evidence in animal models has shown that blockade of A_(2A) receptor function confers antidepressant activity (El Yacoubi, M et al. Br. J. Pharmacol. 2001, 134, 68-77). Thus, A_(2A) receptor antagonists may offer a novel therapy for the treatment of major depression and other affective disorders in patients.

The pharmacology of adenosine A_(2A) receptors has been reviewed (Ongini, E.; Fredholm, B. B. Trends Pharmacol. Sci. 1996, 17(10), 364-372). One potential underlying mechanism in the aforementioned treatment of movement disorders by the blockade of A₂ adenosine receptors is the evidence of a functional link between adenosine A_(2A) receptors to dopamine D₂ receptors in the CNS. Some of the early studies (e.g. Ferre, S. et al., Stimulation of high-affinity adenosine A₂ receptors decreases the affinity of dopamine D₂ receptors in rat striatal membranes. Proc. Natl. Acad. Sci. U.S.A. 1991, 88, 7238-41) have been summarised in two more recent articles (Fuxe, K. et al., Adenosine Adenine Nucleotides Mol. Biol. Integr. Physiol., [Proc. Int. Symp.], 5th (1995), 499-507. Editors: Belardinelli, Luiz; Pelleg, Amir. Publisher: Kluwer, Boston, Mass.; Ferre, S. et al., Trends Neurosci. 1997, 20, 482-487).

As a result of these investigations into the functional role of adenosine A_(2A) receptors in the CNS, especially in vivo studies linking A₂ receptors with catalepsy (Ferre et al., Neurosci. Lett. 1991, 130, 162-4; Mandhane, S. N. et al., Eur. J. Pharmacol. 1997, 328, 135-141) investigations have been made into agents which selectively bind to adenosine A_(2A) receptors as potentially effective treatments for Parkinson's disease.

While many of the potential drugs for treatment of Parkinson's disease have shown benefit in the treatment of movement disorders, an advantage of adenosine A_(2A) antagonist therapy is that the underlying neurodegenerative disorder may also be treated. The neuroprotective effect of adenosine A_(2A) antagonists has been reviewed (Ongini, E.; Adami, M.; Ferri, C.; Bertorelli, R., Ann. N.Y. Acad. Sci. 1997, 825 (Neuroprotective Agents), 30-48). In particular, compelling recent evidence suggests that blockade of A_(2A) receptor function confers neuroprotection against MPTP-induced neurotoxicity in mice (Chen, J-F., J. Neurosci. 2001, 21, RC143). In addition, several recent studies have shown that consumption of dietary caffeine, a known adenosine A_(2A) receptor antagonist, is associated with a reduced risk of Parkinson's disease in man (Ascherio, A. et al, Ann Neurol., 2001, 50, 56-63; Ross G W, et al., JAMA, 2000, 283, 2674-9). Thus, A_(2A) receptor antagonists may offer a novel treatment for conferring neuroprotection in neurodegenerative diseases such as Parkinson's disease.

Xanthine derivatives have been disclosed as adenosine A₂ receptor antagonists as useful for treating various diseases caused by hyperfunctioning of adenosine A₂ receptors, such as Parkinson's disease (see, for example, EP-A-565377).

One prominent xanthine-derived adenosine A_(2A) selective antagonist is CSC [8-(3-chlorostyryl)caffeine] (Jacobson et al., FEBS Lett., 1993, 323, 141-144).

Theophylline (1,3-dimethylxanthine), a bronchodilator drug which is a mixed antagonist at adenosine A₁ and A_(2A) receptors, has been studied clinically. To determine whether a formulation of this adenosine receptor antagonist would be of value in Parkinson's disease an open trial was conducted on 15 Parkinsonian patients, treated for up to 12 weeks with a slow release oral theophylline preparation (150 mg/day), yielding serum theophyilline levels of 4.44 mg/L after one week. The patients exhibited significant improvements in mean objective disability scores and 11 reported moderate or marked subjective improvement (Mally, J., Stone, T. W., J. Pharm. Pharmacol, 1994, 46, 515-517).

KF 17837 [(E)-8-(3′,4-dimethoxystyryl-1,3-dipropyl-7-methylxanthine] is a selective adenosine A_(2A) receptor antagonist which on oral administration significantly ameliorated the cataleptic responses induced by intracerebroventricular administration of an adenosine A_(2A) receptor agonist, CGS 21680. KF 17837 also reduced the catalepsy induced by haloperidol and reserpine. Moreover, KF 17837 potentiated the anticataleptic effects of a subthreshold dose of L-DOPA plus benserazide, suggesting that KF 17837 is a centrally active adenosine A_(2A) receptor antagonist and that the dopaminergic function of the nigrostriatal pathway is potentiated by adenosine A_(2A) receptor antagonists (Kanda, T. et al., Eur. J. Pharmacol. 1994, 256, 263-268). The structure activity relationship (SAR) of KF 17837 has been published (Shimada, J. et al., Bioorg. Med. Chem. Lett. 1997, 7, 2349-2352). Recent data has also been provided on the A_(2A) receptor antagonist KW-6002 (Kuwana, Y et al., Soc. Neurosci. Abstr. 1997, 23, 119.14; and Kanda, T. et al., Ann. Neurol. 1998, 43(4), 507-513).

New non-xanthine structures sharing these pharmacological properties include SCH 58261 and its derivatives (Baraldi, P. G. et al., Pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine Derivatives: Potent and Selective A_(2A) Adenosine Antagonists. J. Med. Chem. 1996, 39, 1164-71). SCH 58261 (7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine) is reported as effective in the treatment of movement disorders (Ongini, E. Drug Dev. Res. 1997, 42(2), 63-70) and has been followed up by a later series of compounds (Baraldi, P. G. et al., J. Med. Chem. 1998, 41(12), 2126-2133).

The foregoing discussion indicates that a potentially effective treatment for movement disorders in humans would comprise agents which act as antagonists at adenosine A_(2A) receptors.

It has now been found that purine derivatives, which are structurally unrelated to known adenosine receptor antagonists, exhibit unexpected antagonist binding affinity at adenosine (P₁) receptors, and in particular at the adenosine A_(2A) receptor. Such compounds may therefore be useful for the treatment of disorders in which the blocking of purine receptors, particularly adenosine receptors and more particularly adenosine A_(2A) receptors, may be beneficial. In particular such compounds may be suitable for the treatment of movement disorders, such as disorders of the basal ganglia which result in dyskinesias. Disorders of particular interest in the present invention include Parkinson's disease, Alzheimer's disease, spasticity, Huntington's chorea and Wilson's disease.

Such compounds may also be particularly suitable for the treatment of depression, cognitive or memory impairment including Alzheimer's disease, acute or chronic pain, ADHD, narcolepsy or for neuroprotection.

According to the present invention there is provided the use of a compound of formula (I):

wherein R₁ is selected from alkyl, aryl, alkoxy, aryloxy, thioalkyl, thioaryl, CN, halo, NR₅R₆, NR₄COR₅, NR₄CONR₅R₆, NR₄CO₂R₇ and NR₄SO₂R₇; R₂ is selected from N, O or S-containing heteroaryl groups, wherein the heteroaryl group is attached via an unsaturated carbon atom which is adjacent to one or two N, O or S-heteroatom(s), other than ortho,ortho-disubstituted heteroaryl groups; R₃ is selected from H, alkyl, COR₈, CONR₉R₁₀, CONR₈NR₉R₁₀, CO₂R₁₁ and SO₂R₁; R₄, R₅ and R₆ are independently selected from H, alkyl and aryl or where R₅ and R₆ are in an (NR₅R₆) group then R₅ and R₆ may be linked to form a heterocyclic group; R₇ is selected from alkyl and aryl; R₈, R₉ and R₁₀ are independently selected from H, alkyl and aryl, or R₉ and R₁₀ may be linked to form a heterocyclic group, or where R₈, R₉ and R₁₀ are in a (CONR₈NR₉R₁₀) group, R₈ and R₉ may be linked to form a heterocyclic group, and R₁₁ is selected from alkyl and aryl, or a pharmaceutically acceptable salt thereof or prodrug thereof, in the manufacture of a medicament for the treatment or prevention of a disorder in which the blocking of purine receptors, particularly adenosine receptors and more particularly A_(2A) receptors, may be beneficial.

As used herein, the term “alkyl” means a branched or unbranched, cyclic or acyclic, saturated or unsaturated (e.g. alkenyl or alkynyl) hydrocarbyl radical which may be substituted or unsubstituted. Where cyclic, the alkyl group is preferably C₃ to C₁₂, more preferably C₅ to C₁₀, more preferably C₅, C₆ or C₇. Where acyclic, the alkyl group is preferably C₁ to C₁₀, more preferably C₁ to C₆, more preferably methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, isobutyl or tertiary-butyl) or pentyl (including n-pentyl and iso-pentyl), more preferably methyl. It will be appreciated therefore that the term “alkyl” as used herein includes alkyl (branched or unbranched), alkenyl (branched or unbranched), alkynyl (branched or unbranched), cycloalkyl, cycloalkenyl and cycloalkynyl.

As used herein, the term “lower alkyl” means methyl, ethyl, propyl (n-propyl or isopropyl) or butyl (n-butyl, isobutyl or tertiary-butyl).

As used herein, the term “aryl” means an aromatic group, such as phenyl or naphthyl (preferably phenyl), or a heteroaromatic group containing one or more heteroatom(s) preferably selected from N, O and S, such as pyridyl, pyrrolyl, quinolinyl, furanyl, thienyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, imidazolyl, pyrimidinyl, indolyl, pyrazinyl or indazolyl.

As used herein, the term “heteroaryl” means an aromatic group containing one or more heteroatom(s) preferably selected from N, O and S, such as pyridyl, pyrrolyl, quinolinyl, furanyl, thienyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, imidazolyl, pyrimidinyl, indolyl, pyrazinyl or indazolyl.

As used herein, the term “non-aromatic heterocyclyl” means a non-aromatic cyclic group containing one or more heteroatom(s) preferably selected from N, O and S, such as a cyclic amino group (including aziridinyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, morpholinyl) or a cyclic ether (including tetrahydrofuranyl).

As used herein, the term “alkoxy” means alkyl-O—. As used herein, the term “aryloxy” means aryl-O—.

As used herein, the term “halogen” means a fluorine, chlorine, bromine or iodine radical.

As used herein, the term “ortho,ortho-disubstituted heteroaryl groups” refers to heteroaryl groups which are substituted in both ortho positions of the heteroaryl group relative to the point of attachment of the heteroaryl group to the purine ring.

As used herein, the term “prodrug” means any pharmaceutically acceptable prodrug of a compound of the present invention.

Where any of R₁ to R₁₂₀ is selected from alkyl, alkoxy and thioalkyl, in accordance with formula (I) as defined above, then that alkyl group, or the alkyl group of the alkoxy or thioalkyl group, may be substituted or unsubstituted. Where any of R₁ to R₂₀ are selected from aryl, aryloxy and thioaryl, in accordance with formula (I) as defined above, then said aryl group, or the aryl group of the aryloxy or thioaryl group, may be substituted or unsubstituted. Where R₅ and R₆, or R₉ and R₁₀, or R₈ and R₉, or R₁₄ and R₁₅, are linked to form a heterocyclic group in accordance with formula (I) as defined above, then said heterocyclic ring may be substituted or unsubstituted. Where substituted, there will generally be 1 to 3 substituents present, preferably 1 substituent. Substituents may include: carbon-containing groups such as

-   -   alkyl,     -   aryl, (e.g. substituted and unsubstituted phenyl, including         (alkyl)phenyl, (alkoxy)phenyl and halophenyl),     -   arylalkyl; (e.g. substituted and unsubstituted benzyl, including         alkylbenzyl);         halogen atoms and halogen containing groups such as     -   haloalkyl (e.g. trifluoromethyl),     -   haloaryl (e.g. chlorophenyl);         oxygen containing groups such as     -   alcohols (e.g. hydroxy, hydroxyalkyl, hydroxyaryl,         (aryl)(hydroxy)alkyl),     -   ethers (e.g. alkoxy, aryloxy, alkoxyalkyl, aryloxyalkyl,         alkoxyaryl, aryloxyaryl),     -   aldehydes (e.g. carboxaldehyde),     -   ketones (e.g. alkylcarbonyl, arylcarbonyl, alkylcarbonylalkyl,         alkylcarbonylaryl, arylcarbonylalkyl, arylcarbonylaryl,         arylalkylcarbonyl, arylalkylcarbonylalkyl,         arylalkylcarbonylaryl)     -   acids (e.g. carboxy, carboxyalkyl, carboxyaryl),     -   acid derivatives such as esters         -   (e.g. alkoxycarbonyl, aryloxycarbonyl, alkoxycarbonylalkyl,             aryloxycarbonylalkyl, alkoxycarbonylaryl,             aryloxycarbonylaryl, alkylcarbonyloxy,             alkylcarbonyloxyalkyl), amides         -   (e.g. aminocarbonyl, mono- or di-alkylaminocarbonyl,             cyclicaminocarbonyl, aminocarbonylalkyl, mono- or             di-alkylaminocarbonylalkyl, arylaminocarbonyl or             arylalkylaminocarbonyl, alkylcarbonylamino,             arylcarbonylamino, arylalkylcarbonylamino,             alkylcarbonylaminoalkyl, arylcarbonylaminoalkyl or             arylalkylcarbonylaminoalkyl), carbamates         -   (eg. alkoxycarbonylamino, aryloxycarbonylamino,             arylalkyloxycarbonylamino, aminocarbonyloxy, mono- or             di-alkylaminocarbonyloxy, arylaminocarbonyloxy or             arylalkylaminocarbonyloxy) and ureas         -   (eg. mono- or di-alkylaminocarbonylamino,             arylaminocarbonylamino or arylalkylaminocarbonylamino);             nitrogen containing groups such as     -   amines (e.g. amino, mono- or dialkylamino, cyclicamino,         arylamino, aminoalkyl, mono- or dialkylaminoalkyl), azides,     -   nitriles (e.g. cyano, cyanoalkyl),     -   nitro;     -   sulfonamides (e.g. aminosulfonyl, mono- or         di-alkylaminosulfonyl, mono- or di-arylaminosulfonyl, alkyl- or         aryl-sulfonylamino, alkyl- or aryl-sulfonyl(alkyl)amino, alkyl-         or aryl-sulfonyl(aryl)amino)         sulfur containing groups such as     -   thiols, thioethers, sulfoxides, and sulfones         -   (e.g. alkylthio, alkylsulfinyl, alkylsulfonyl,             alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl,             arylthio, arylsulfinyl, arylsulfonyl, arylthioalkyl,             arylsulfinylalkyl, arylsulfonylalkyl);             heterocyclic groups containing one or more, preferably one,             heteroatom,     -   (e.g. thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl,         thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiadiazolyl,         aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl,         imidazolidinyl, imidazolinyl, pyrazolidinyl, tetrahydrofuranyl,         pyranyl, pyronyl, pyridyl, pyrazinyl, pyridazinyl, piperidyl,         hexahydroazepinyl, piperazinyl, morpholinyl, thianaphthyl,         benzofuranyl, isobenzofuranyl, indolyl, oxyindolyl, isoindolyl,         indazolyl, indolinyl, 7-azaindolyl, benzopyranyl, coumarinyl,         isocoumarinyl, quinolinyl, isoquinolinyl, naphthridinyl,         cinnolinyl, quinazolinyl, pyridopyridyl, benzoxazinyl,         quinoxalinyl, chromenyl, chromanyl, isochromanyl, phthalazinyl         and carbolinyl); and         silicon-containing groups such as     -   silanes (e.g. trialkylsilyl).

Where any of R₁ to R₂₀ is selected from aryl or from an aryl-containing group such as aryloxy or arylthio, preferred substituent group(s) are selected from halogen, alkyl (substituted or unsubstituted; and where substituted particularly from alkoxyalkyl, hydroxyalkyl, aminoalkyl and haloalkyl), hydroxy, alkoxy, CN, NO₂, amines (including amino, mono- and di-alkylamino), alkoxycarbonyl, aminocarbonyl, carboxamido, sulfonamido, alkoxycarbonylamino and aryl, and particularly from unsubstituted alkyl, substituted alkyl (including alkoxyalkyl and aminoalkyl), halogen and amines.

In one embodiment, where any of R₁ to R₂₀ is directly substituted by an alkyl substituent group, or by an alkyl-containing substituent group (such as alkoxy or alkylcarbonylamino for example), then the alkyl moiety of the substituent group directly attached to any of R₁ to R₂₀ may be further substituted by the substituent groups hereinbefore described and particularly by halogen, hydroxy, alkoxy, CN, amines (including amino, mono- and di-alkyl amino) and aryl.

In a further embodiment, where any of R₁ to R₂₀ is directly substituted by an aryl substitutent group, or by an aryl-containing substituent group (such as aryloxy or arylaminocarbonylamino for example), then the aryl moiety of the substituent group directly attached to any of R₁ to R₂₀ may be further substituted by the substituent groups hereinbefore described and particularly by halogen, alkyl (substituted or unsubstituted; and where substituted particularly from alkoxyalkyl, hydroxyalkyl, aminoalkyl and haloalkyl), hydroxy, alkoxy, CN, NO₂, amines (including amino, mono- and di-alkylamino), alkoxycarbonyl, aminocarbonyl, carboxamido, sulfonamido, alkoxycarbonylamino and aryl. In a further embodiment, said aryl moiety is substituted by halogen, alkyl (including CF₃), hydroxy, alkoxy, CN, amines (including amino, mono- and di-alkyl amino) and NO₂. In a further embodiment, said aryl moiety is substituted by unsubstituted all, substituted alkyl (particularly alkoxyalkyl and aminoalkyl), halogen and amines.

The terms “directly substituted” and “directly attached”, as used herein, mean that the substituent group is bound directly to any of R₁ to R₂₀ without any intervening divalent atoms or groups.

In the compounds of formula (I), R₁ is selected from alkyl (including haloalkyl (such as CF₃), branched alkyl, cycloalkyl and arylalkyl), aryl (including heteroaryl), alkoxy, aryloxy, thioalkyl, thioaryl, halo, CN, NR₅R₆ (including NH₂), NR₄COR₅, NR₄CONR₅R₆, NR₄CO₂R₇ and NR₄SO₂R₇.

In a preferred embodiment, R₁ is selected from NR₅R₆ (including NH₂), alkoxy, thioalkyl and alkyl.

In a particularly preferred embodiment, R₁ is selected from NR₅R₆ (including NH₂), and is preferably NH₂.

Where R₁ is selected from alkyl, preferably R₁ is selected from C₁₋₆ alkyl, more preferably from saturated C₁₋₆ alkyl and more preferably from lower alkyl.

Where R₁ is selected from alkoxy and thioalkyl, preferably the alkyl moiety of said thioalkyl or alkoxy group is selected from C₁₋₆ alkyl, more preferably from saturated C₁₋₆ alkyl and more preferably from lower alkyl.

Where R₁ is selected from halo, preferably R₁ is selected from chloro.

Where R₁ is selected from NR₅R₆, preferably at least one and more preferably both of R₅ and R₆ are hydrogen.

In one embodiment, R₁ is selected from NR₄COR₅, NR₄CONR₅, NR₄CO₂R₇ and R₄SO₂R₇, and R₄ is selected from H and alkyl, and more preferably hydrogen.

In a preferred embodiment, R₂ is selected from furyl (including 2-furyl), thienyl (including 2-thienyl), pyridyl (including 2-pyridyl), thiazolyl (including 2- and 5-thiazolyl), pyrazolyl (including 3-pyrazolyl), triazolyl (including 4-triazolyl), pyrrolyl (including 2-pyrrolyl) and oxazolyl (including 5-oxazolyl). In a further embodiment, R₂ is selected from 2-furyl, 2-thienyl, 2-thiazolyl, 2-pyridyl, 3-pyrazolyl, 2-pyrrolyl, 4-triazolyl and 5-oxazolyl. In a further preferred embodiment, R₂ is selected from furyl, thienyl, pyridyl, thiazolyl and pyrazolyl, and particularly from 2-furyl, 2-thienyl, 2-thiazolyl, 2-pyridyl and 3-pyrazolyl. In a further embodiment, R₂ is selected from furyl, thienyl and pyridyl, preferably 2-furyl, 2-thienyl and 2-pyridyl, and more preferably from 2-furyl.

In the compounds of formula (I), where R₂ is substituted heteroaryl, it is preferred that the substituent group(s) are not present in the ortho position relative to the point of attachment of the heteroaryl group to the purine moiety. As used herein, reference to ortho-substitution of the R₂ group means the ortho positions of the R₂ group relative to the point of attachment of R₂ to the pyrimidine moiety of formula (I).

In a preferred embodiment, R₂ is an unsubstituted heteroaryl group.

In the compounds of formula (I), R₃ is selected from H, substituted and unsubstituted alkyl (including saturated alkyl, alkenyl, alkynyl, branched and unbranched alkyl, and cyclic and acyclic alkyl), COR₈, CONR₉R₁₀, CONR₈NR₉R₁₀, CO₂R₁ and SO₂R₁₁.

In a preferred embodiment, R₃ is selected from H, alkyl and CONR₉R₁₁.

In a particularly preferred embodiment, R₃ is selected from H, substituted alkyl and CONR₉R₁₀. In an alternative embodiment, R₃ is selected from alkyl (substituted or unsubstituted) and CONR₉R₁₀, preferably substituted alkyl and CONR₉R₁₀. Wherein R₃ is substituted alkyl, said substituted alkyl is preferably selected from arylalkyl (including heteroarylalkyl) and alkyl substituted by CONR₉R₁₀, and more preferably from arylalkyl (including heteroarylalkyl), and more preferably from arylmethyl (including heteroarylmethyl).

Where R₃ is selected from COR₈, R₈ is preferably selected from alkyl (including cycloalkyl) and aryl (including heteroaryl), preferably from saturated C₁₋₆ alkyl (including cycloalkyl) and aryl.

Where R₃ is selected from CONR₉R₁₀, it is preferred that R₉ and R₁₀ are selected from H, C₁₋₆ alkyl and aryl, and preferably from H, C₁₋₆ saturated alkyl (including cycloalkyl) and aryl, and more preferably from H, lower alkyl and aryl. Preferably one of R₉ and R₁₀ is hydrogen. Where R₉ or R₁₀ is aryl, it is preferred that said aryl is substituted or unsubstituted phenyl. Where R₉ or R₁₀ is lower alkyl, said lower alkyl may be substituted by hydroxy, halo, alkoxy, dialkylamino, substituted or unsubstituted aryl, preferably by substituted or unsubstituted aryl (including heteroaryl), more preferably by substituted and unsubstituted phenyl, thienyl, furyl and pyridyl, and more preferably by substituted phenyl, thienyl, furyl and pyridyl.

In a preferred embodiment, R₃ is CONR₉R₁₀, R₉ is H and R₁₀ is selected from C₁₋₆ saturated alkyl, preferably saturated lower alkyl and preferably methyl, preferably substituted by substituted or unsubstituted aryl (including heteroaryl), more preferably substituted by phenyl, thienyl, furyl and pyridyl.

Where R₃ is selected from CO₂R₁₁, preferably R₁₁ is selected from C₁₋₆ alkyl, preferably saturated C₁₋₆ alkyl, preferably saturated C₁₋₆ alkyl, and more preferably lower alkyl, optionally substituted by one or more (preferably one) substituent group preferably selected from aryl.

Where R₃ is selected from SO₂R₁₁ it is preferred that R₁ is selected from C₁₋₆ alkyl (including cycloalkyl and alkenyl) and aryl (including heteroaryl). Where R₃ is SO₂R₁₁ and R₁₁ is aryl, the aryl group may be substituted or unsubstituted, preferably substituted, and preferably substituted by lower alkyl or halo groups.

Where R₃ is selected from alkyl, in one embodiment R₃ is selected from acyclic alkyl (substituted or unsubstituted). In a further embodiment, R₃ is selected from substituted or unsubstituted C₁₋₆ alkyl (preferably acyclic, and including alkenyl and alkynyl), preferably from substituted or unsubstituted C₁₋₆ saturated alkyl and alkenyl (preferably acyclic), more preferably from substituted or unsubstituted C₁₋₆ saturated alkyl (preferably acyclic), preferably substituted or unsubstituted lower alkyl, more preferably from substituted or unsubstituted methyl, ethyl and propyl (n-propyl or isopropyl) groups, and more preferably from substituted or unsubstituted methyl.

In a preferred embodiment, R₃ is selected from substituted alkyl, preferably mono-substituted alkyl where said substituent(s) is/are represented by R₁₂. Preferably, R₁₂ is selected from hydroxy, alkoxy, dialkylamino, NH₂, aryloxy, CN, halo, cycloalkyl, aryl (including heteroaryl), non-aromatic heterocyclyl, COR₁₃, CONR₁₄R₁₅, CONR₈NR₉R₁₀, C(═NR₁₃)NR₁₄R₁₅, NR₁₃COR₁₄, NR₁₃CO₂R₁₁, trialkylsilyl and phthalimido, wherein R₁₃, R₁₄ and R₁₅ are selected from hydrogen, alkyl and aryl, or where R₁₄ and R₁₅ are in an (NR₁₄R₁₅)group, R₁₄ and R₁₅ may be linked to form a heterocyclic ring. Preferably, R₁₂ is selected from aryl (including heteroaryl) and CONR₁₄R₁₅, and preferably from aryl (including heteroaryl).

Where R₁₂ is CONR₁₄R₁₅, it is preferred that R₁₄ and R₁₅ are selected from H, C₁₋₆ alkyl and aryl, preferably from H, C₁₋₆ saturated alkyl (including cycloalkyl and arylalkyl (including heteroaryl)) and aryl (including heteroaryl) and more preferably from H, lower alkyl and aryl. Preferably one of R₁₄ and R₁₅ is hydrogen.

In one embodiment, R₁₂ is CONR₁₄R₁₅ and R₁₄ and/or R₁₅ are selected from alkyl substituted by one or more, preferably one, substituent group(s) selected from hydroxy, alkoxy and dialkylamino.

Where R₁₂ is selected from aryl (including heteroaryl), the aryl group may be unsubstituted or substituted, and is preferably substituted. In a preferred embodiment, R₁₂ is selected from mono-, di- or tri-substituted aryl (including heteroaryl) groups. Where R₁₂ is heteroaryl, R₁₂ is preferably selected from mono or bicyclic heteroaryl groups, more preferably from pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, preferably 2-pyridyl), indolyl (including 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl and 7-indolyl), furyl (including 2-furyl and 3-furyl, preferably 2-furyl), thienyl (including 2-thienyl and 3-thienyl, preferably 2-thienyl), isoindolyl, indolinyl, isoxazolyl, oxazolyl, thiazolyl, pyrazinyl, pyrimidinyl, quinolinyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, indazolyl, benzodioxolyl and dihydrobenzofuranyl, more preferably from pyridyl (preferably 2-pyridyl), indolyl, furyl (preferably 2-furyl) and thienyl (preferably 2-thienyl), and most preferably from pyridyl (preferably 2-pyridyl), furyl (preferably 2-furyl) and thienyl (preferably 2-thienyl). Preferably, R₁₂ is selected from phenyl, thienyl, furyl and pyridyl, more preferably from phenyl, 2-thienyl, 2-furyl and 2-pyridyl In a preferred embodiment, R₁₂ is phenyl.

In one embodiment, R₁₂ is selected from mono-, di- or tri-substituted aryl (including heteroaryl) groups represented by the formula Ar(R₁₈)_(a)(R₁₉)_(b)(R₂₀)_(c) wherein Ar is an aryl (including heteroaryl) group, preferably selected from the preferred aryl groups described above for R₁₂; wherein R₁₈, R₁₉ and R₂₀ are substituent group(s), the same or different; and wherein a, b and c are 0 or 1 such that a+b+c≧1.

The substituent groups R₁₈, R₁₉ and R₂₀ may be selected from any of the substituent groups described herein above.

In a preferred embodiment, R₁₈, R₁₉ and R₂₀ are selected from NR₅R₆ (including NH₂, and NHR₅) alkyl (substituted or unsubstituted; preferably C₁₋₆ acyclic alkyl), alkoxy (including fluoroalkoxy), halogen (including F, Cl, Br and I), NO₂, CN, hydroxy, NHOH, CHO, CONR₅R₆, CO₂R₅, N COR₅ (preferably NHCOR₅), NR₄CO₂R₇ (preferably NHCO₂R₇), NR₄SO₂R₇ (preferably NHSO₂R₇), OCO₂R₇ and aryl (including heteroaryl).

In a more preferred embodiment, R₁₈, R₁₉ and R₂₀ are selected from NR₅R₆ (including NH₂ and NHR₅), alkyl (substituted or unsubstituted; and preferably C₁₋₆ acyclic saturated alkyl) and halogen (preferably F or Cl, particularly F).

In a particularly preferred embodiment, R₁₈, R₁₉ and R₂₀ are selected from NR₅ (including NH₂ and NHR₅, preferably NH₂) and alkyl (substituted or unsubstituted; preferably C₁₋₆ acyclic saturated alkyl).

Where R₁₈, R₁₉ and R₂₀ are selected from substituted alkyl, said alkyl is preferably selected from alkoxyalkyl, hydroxyalkyl, aminoalkyl (including NH₂-alkyl, mono-alkylaminoalkyl and di-alkylaminoalkyl), haloalkyl (particularly fluoroalkyl (including CF₃)), cyanoalkyl, alkylthioalkyl, alkylcarboxyaminoalkyl, alkoxycarbonylaminoalkyl and alkylsulfonylamino, more preferably from alkoxyalkyl, hydroxyalkyl, aminoalkyl and haloalkyl (particularly fluoroalkyl (including CF₃)) and most preferably from alkoxyalkyl and aminoalkyl.

In one embodiment, particularly where R₁₂ is aryl, preferably phenyl, the substituent groups R₁₈, R₁₉ and R₂₀ are selected from lower alkyl, hydroxy, lower alkoxy, amino (including NH₂, mono and di-alkylamino), NO₂, CN, amido, aminocarbonyl (including mono- and di-alkylaminocarbonyl), sulfonamido or halo group(s). In a further embodiment R₁₂ is aryl, preferably phenyl, substituted by NR₁₆SO₂R₁₇ wherein R₁₆ is selected from H, alkyl and aryl and preferably H, and R₁₇ is selected from alkyl and aryl, preferably from C₁₋₆ saturated alkyl and aryl (including heteroaryl). R₁₇ may be unsubstituted or substituted, for instance by alkyl or hydroxy.

In the compounds of formula (I) R₄, R₅, R₆, R₈, R₉, R₁₀, R₁₃, R₁₄ and R₁₅ are independently selected from H, substituted and unsubstituted alkyl (including saturated alkyl, alkenyl, alkenyl, branched and unbranched alkyl, and cyclic and acyclic alkyl) and substituted and unsubstituted aryl (including heteroaryl), or where R₅ and R₆ are in an (NR₅R₆) group then R₅ and R₆ may be linked to form a heterocyclic group, or where R₉ and R₁₀ are in an (NR₉R₁₀) group then R₉ and R₁₀ may be linked to form a heterocyclic group, or where R₈, R₉ and R₁₀ are in a (CONR₈NR₉R₁₀) group, R₈ and R₉ may be linked to form a heterocyclic group, or where R₁₄ and R₁₅ are in an (NR₁₄R₁₅)group, R₁₄ and R₁₅ may be linked to form a heterocyclic group. Preferably, R₁₄, R₁₃ and R₁₆ are independently selected from H and alkyl.

In the compounds of formula (I), R₇, R₁₁ and R₁₇ are independently selected from substituted and unsubstituted alkyl (including saturated alkyl, alkenyl, alkenyl, branched and unbranched alkyl and cyclic and acyclic alkyl) and substituted and unsubstituted aryl (including heteroaryl).

Where R₄, R₅, R₆, R₇, R₁₃ and R₁₆ are independently selected from alkyl (substituted or unsubstituted), said alkyl group is preferably selected from C₁₋₆ alkyl, and preferably from C₁₋₆ saturated alkyl and C₁₋₆ alkenyl. In one embodiment, R₄ to R₇, R₁₃ and R₁₆ are selected from C₁₋₆ saturated alkyl, preferably lower alkyl

Where R₄, R₅, R₆, R₇, R₁₃ and R₁₆ are independently selected from substituted alkyl (including saturated alkyl, alkenyl and alkynyl), the one or more substituent group(s) are preferably selected from cycloalkyl, substituted and unsubstituted aryl (including heteroaryl), non-aromatic heterocyclyl, hydroxy, alkoxy and dialkylamino.

Where R₅ and R₆, or R₉ and R₁₀, or R₈ and R₉, or R₁₄ and R₁₅, in accordance with the definitions herein, are linked to form a heterocyclic ring, said heterocyclic ring may be saturated, partially unsaturated or aromatic, and is preferably saturated. Said heterocyclic ring preferably is a 5, 6 or 7-membered ring, preferably a 5 or 6-membered ring, and may contain one or more further heteroatoms preferably selected from N, O and S heteroatoms.

In a particularly preferred embodiment of the invention, the compounds of formula (I) are selected from those compounds wherein R₁ is NH₂, R₂ is 2-furyl and R₃ is arylalkyl (including heteroarylalkyl), particularly arylmethyl (including heteroarylmethyl).

In a particularly preferred embodiment of the invention, the compounds of the present invention are selected from:

-   N,N-Dimethyl-6-(2-furyl)-1H-purine-2-amine; -   6-(2-furyl)-1H-purine-2-amine; -   6-(2-Furyl)-2-methylthio-1H-purine; -   2-Amino-N-benzyl-6-(2-furyl)-9H-purine-9-carboxamide; -   2-Amino-N-n-butyl-6-(2-furyl)-9H-purine-9-carboxamide; -   2-Amino-6-(2-furyl)-N-(4-methoxybenzyl)-9H-purine-9-carboxamide; -   2-Amino-6-(2-furyl)-N-(4-methylbenzyl)-9H-purine-9-carboxamide; -   2-Amino-N-(2-chlorobenzyl)-6-(2-furyl)-9H-purine-9-carboxamide; -   (1S)-2-Amino-6-(2-furyl)-N-(1-phenylethyl)-9H-purine-9-carboxamide; -   2-Amino-6-(2-furyl)-N-(3-methylbenzyl)-9H-purine-9-carboxamide; -   2-Amino-6-(2-furyl)-N-n-pentyl-9H-purine-9-carboxamide; -   6-(2-Furyl)-9-(1-phenyl-1-propene-3-yl)-9H-purine-2-amine; -   6-(2-Furyl)-9-(3-phenylpropyl)-9H-purine-2-amine; -   2-Amino-N-(4-fluorobenzyl)-6-(2-furyl)-9H-purine-9-carboxamide; -   2-Amino-N-(3,4-dichlorobenzyl)-6-(2-furyl)-9H-purine-9-carboxamide; -   6-(2-Furyl)-9-(4-isopropylbenzyl)-9H-purine-2-amine; -   2-Amino-6-(2-furyl)-N-(2-phenylethyl)-9H-purine-9-carboxamide; -   2-Amino-N-(2,4-dichlorobenzyl)-6-(2-furyl)-9H-purine-9-carboxamide; -   Benzyl 2-amino-6-(2-furyl)-9H-purine-9-carboxylate; -   N-Benzyl-2-methoxy-6-(2-furyl)-9H-purine-9-carboxamide; -   2-Amino-N-benzyl-6-(2-furyl)-N-methyl-9H-purine-9-carboxamide; -   9-(3-Chlorobenzyl)-6-(2-furyl)-9H-purine-2-amine; -   6-(2-Furyl)-9-(3-methylbenzyl)-9H-purine-2-amine; -   6-(2-Furyl)-9-(4-methylbenzyl)-9H-purine-2-amine; -   2-Amino-N-(3-chlorophenyl)-6-(2-furyl)-9H-purine-9-acetamide; -   9-(2-Fluorobenzyl)-6-(2-furyl)-9H-purine-2-amine; -   6-(2-Furyl)-9-(4-trifluoromethylbenzyl)-9H-purine-2-amine; -   9-(4-Bromophenyl)sulphonyl-6-(2-furyl)-9H-purine-2-amine; -   6-(2-Furyl)-9-(2-phenylethenyl)sulphonyl-9H-purine-2-amine; -   6-(2-Furyl)-9-(3-(3-pyridyl)propyl)-9H-purine-2-amine; -   9-(3-Aminobenzyl)-6-(2-furyl)-9H-purine-2-amine; -   6-(2-Furyl)-9-(3-methoxybenzyl)-9H-purine-2-amine; -   2-Amino-6-(2-furyl)-N-(2-furylmethyl)-9H-purine-9-carboxamide; -   2-Amino-6-(2-furyl)-N-(2-thienylmethyl)-9H-purine-9-carboxamide; -   9-(4-Methylbenzyl)-6-(5-methyl-2-furyl)-9H-purine-2-amine; -   9-(2,6-Difluorobenzyl)-6-(2-furyl)-9H-purine-2-amine; -   6-(2-Furyl)-9-(6-methyl-2-pyridyl)methyl-9H-purine-2-amine; -   6-(2-Furyl)-9-(2-(1-methyl-1H-imidazol-4-ylsulphonylamino)benzyl)-9H-purine-2-amine; -   9-(5-Chloro-2-thienylmethyl)-6-(2-furyl)-9H-purine-2-amine; -   9-(2-Fluorobenzyl)-6-(4-methyl-2-thiazolyl)-9H-purine-2-amine; and -   9-(2-Fluoro-5-nitrobenzyl)-6-(2-furyl)-9H-purine-2-amine.

Where chiral the compounds of the formula (I) may be in the form of a racemic mixture of pairs of enantiomers or in enantiomerically pure form.

The present invention may be employed in respect of a human or animal subject, more preferably a mammal, more preferably a human subject.

According to a further aspect of the present invention there is provided a method of treating or preventing a disorder in which the blocking of purine receptors, particularly adenosine receptors and more particularly adenosine A_(2A) receptors, may be beneficial, the method comprising administration to a subject in need of such treatment an effective dose of a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof.

The disorder may be caused by the hyperfunctioning of the purine receptors.

The disorders of particular interest are those in which the blocking of purine receptors, partiucularly adenosine receptors and more particularly adenosine A_(2A) receptors, may be beneficial. These may include movement disorders such as Parkinson's disease, drug-induced Parkinsonism, post-encephalitic Parkinsonism, Parkinsonism induced by poisoning (for example MPTP, manganese, carbon monoxide) and post-traumatic Parkinson's disease (punch-drunk syndrome).

Other movement disorders in which the blocking of purine receptors, may be of benefit include progressive supernuclear palsy, Huntingtons disease, multiple system atrophy, corticobasal degeneration, Wilsons disease, Hallerrorden-Spatz disease, progressive pallidal atrophy, Dopa-responsive dystonia-Parkinsonism, spasticity or other disorders of the basal ganglia which result in abnormal movement or posture. The present invention may also be effective in treating Parkinson's with on-off phenomena; Parkinson's with freezing (end of dose deterioration); and Parkinson's with prominent dyskinesias.

The compounds of formula (I) may be used or administered in combination with one or more additional drugs useful in the treatment of movement disorders, such as L-DOPA or a dopamine agonist, the components being in the same formulation or in separate formulations for administration simultaneously or sequentially.

Other disorders in which the blocking of purine receptors, particularly adenosine receptors and more particularly adenosine A_(2A) receptors may be beneficial include acute and chronic pain; for example neuropathic pain, cancer pain, trigeminal neuralgia, migraine and other conditions associated with cephalic pain, primary and secondary hyperalgesia, inflammatory pain, nociceptive pain, tabes dorsalis, phantom limb pain, spinal cord injury pain, central pain, post-herpetic pain and HIV pain; affective disorders including mood disorders such as bipolar disorder, seasonal affective disorder, depression, manic depression, atypical depression and monodepressive disease; central and peripheral nervous system degenerative disorders including corticobasal degeneration, demyelinating disease (multiple sclerosis, disseminated sclerosis), Freidrich's ataxia, motoneurone disease (amyotrophic lateral sclerosis, progressive bulbar atrophy), multiple system atrophy, myelopathy, radiculopathy, peripheral neuropathy (diabetic neuropathy, tabes dorsalis, drug-induced neuropathy, vitamin deficiency), systemic lupus erythamatosis, granulomatous disease, olivo-ponto-cerebellar atrophy, progressive pallidal atrophy, progressive supranuclear palsy, spasticity; schizophrenia and related pyshoses; cognitive disorders including dementia, Alzheimers Disease, Frontotemporal dementia, multi-infarct dementia, AIDS dementia, dementia associated with Huntingtons Disease, Lewy body dementia, senile dementia, age-related memory impairment, cognitive impairment associated with dementia, Korsakoff syndrome, dementia pugilans; attention disorders such as attention-deficit hyperactivity disorder (ADHD), attention deficit disorder, minimal brain dysfunction, brain-injured child syndrome, hyperkinetic reaction childhood, and hyperactive child syndrome; central nervous system injury including traumatic brain injury, neurosurgery (surgical trauma), neuroprotection for head injury, raised intracranial pressure, cerebral oedema, hydrocephalus, spinal cord injury; cerebral ischaemia including transient ischaemic attack, stroke (thrombotic stroke, ischaemic stroke, embolic stroke, haemorrhagic stroke, lacunar stroke) subarachnoid haemorrhage, cerebral vasospasm, neuroprotection for stroke, peri-natal asphyxia, drowning, cardiac arrest, subdural haematoma; myocardial ischaemia; muscle ischaemia; sleep disorders such as hypersomnia and narcolepsy; eye disorders such as retinal ischaemia-reperfusion injury and diabetic neuropathy; cardiovascular disorders such as claudication and hypotension; and diabetes and its complications.

According to a further aspect of the present invention there is provided use of a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof in the manufacture of a medicament for the treatment or prevention of movement disorders in a subject.

According to a further aspect of the invention there is provided a method of treating or preventing movement disorders comprising administration to a subject in need of such treatment an effective dose of a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof.

According to a further aspect of the invention there is provided use of a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof in the manufacture of a medicament for neuroprotection in a subject.

According to a further aspect of the invention there is provided a method of neuroprotection comprising administration to a subject in need of such treatment an effective dose of a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof.

The medicament for or method of neuroprotection may be of use in the treatment of subjects who are suffering from or at risk from a neurodegenerative disorder, such as a movement disorder.

According to a further aspect of the invention, there is provided for use in therapy a compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof, other than:

-   -   (i) compounds wherein R₁ is halogen or aryl and R₃ is benzyl,         and preferably other than compounds wherein R₁ is halogen or         aryl; and     -   (ii) compounds wherein R₃ is H, R₁ is NH₂ and R₂ is thienyl,         preferably other than compounds wherein R₃ is H and R₁ is NH₂,         and preferably other than compounds wherein R₃ is H.

According to a further aspect of the invention, there is provided for use in therapy a compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof, other than:

-   -   (i) compounds wherein R₁ is halogen or aryl and R₃ is benzyl,         and preferably other than compounds wherein R₁ is halogen or         aryl; and     -   (ii) compounds wherein R₃ is H, R₁ is NH₂ and R₂ is thienyl,         preferably other than compounds wherein R₃ is H and R₂ is         thienyl, and preferably other than compounds wherein R₂ is         thienyl.

In an alternative embodiment, there is provided for use in therapy a compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof, wherein:

R₁ is selected from NR₅R₆ (including NH₂), alkoxy, thioalkyl and alkyl, preferably wherein R₁ is selected from NR₅R₆, and more preferably wherein R₁ is NH₂, and

R₃ is selected from alkyl and CONR₉R₁₀, preferably wherein R₃ is selected from substituted alkyl and CONR₉R₁₀, more preferably wherein R₃ is selected from substituted alkyl and CONR₉R₁₀ wherein said substituted alkyl is selected from arylalkyl (including heteroarylalkyl) and alkyl substituted by CONR₉R₁₀.

According to a further aspect of the present invention there is provided a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof, per se, other than:

-   -   (i) compounds wherein R₁ is halogen or aryl and R₃ is benzyl,         and preferably other than compounds wherein R₁ is halogen or         aryl; and     -   (ii) compounds wherein R₃ is H, R₁ is NH₂ and R₂ is thienyl,         preferably other than compounds wherein R₃ is H and R₁ is NH₂,         and preferably other than compounds wherein R₃ is H.

According to a further aspect of the invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof, per se, other than:

-   -   (i) compounds wherein R₁ is halogen or aryl and R₃ is benzyl,         and preferably other than compounds wherein R₁ is halogen or         aryl; and     -   (ii) compounds wherein R₃ is H, R₁ is NH₂ and R₂ is thienyl,         preferably other than compounds wherein R₃ is H and R₂ is         thienyl, and preferably other than compounds wherein R₂ is         thienyl.

In an alternative embodiment, there is provided a compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof, per se, wherein:

R₁ is selected from NR₅R₆ (including NH₂), alkoxy, thioalkyl and alkyl, preferably wherein R₁ is selected from NR₅R₆, and more preferably wherein R₁ is NH₂, and

R₃ is selected from alkyl and CONR₉R₁₀, preferably wherein R₃ is selected from substituted alkyl and CONR₉R₁₀, more preferably wherein R₃ is selected from substituted alkyl and CONR₉R₁₀ wherein said substituted alkyl is selected from arylalkyl (including heteroarylalkyl) and alkyl substituted by CONR₉R₁₀.

According to a further aspect of the invention, there is provided a method of preparing the novel compounds of the present invention. Compounds of formula (I) may be prepared according to conventional synthetic methods, such as set out in Reaction Scheme 1.

Compounds of formula (1) where R₃ is alkyl (including arylalkyl, heteroarylalkyl and other substituted alkyl) may be prepared from a compound of formula (2) by standard methods such as reaction with an appropriate alkyl halide, or substituted alkyl halide in the presence of a suitable base such as sodium hydride.

Compounds of formula (1) where R₃ is alkyl substituted with R₁₂ wherein R₁₂ is CONR₁₄R₁₅ or CONR₈NR₉R₁₀ may be prepared from compounds of formula (1) where R₃ is alkyl substituted with R₁₂ wherein R₁₂ is CO₂R₁₃ by standard methods such as direct reaction with an appropriate amine or hydrazine or by initial hydrolysis of the ester group CO₂R₁₃ to a carboxylic acid followed by reaction with an appropriate amine or hydrazine in the presence of a standard coupling reagent such as DCC.

Compounds of formula (1) where R₃ is alkyl substituted with R₁₂ wherein R₁₂ is C(═NR₁₃)NR₁₄R₁₅ may be prepared from compounds of formula (1) where R₃ is alkyl substituted with R₁₂ wherein R₁₂ is CN by standard methods such as treatment with an appropriate amine in the presence of trimethylaluminium.

Compounds of formula (1) where R₃ is alkyl substituted with R₁₂ wherein R₁₂ is CO₂R₁₃ or CN may be prepared from compounds of formula (2) by standard methods such as treatment with an appropriate substituted alkyl halide in the presence of a suitable base such as sodium hydride.

Compounds of formula (1) where R₃ is alkyl substituted with R₁₂ wherein R₁₂ is NR₁₃COR₁₄, NR₁₃CO₂R₁₇ or NR₁₃SO₂R₁₇ may be prepared from compounds of formula (1) where R₃ is alkyl substituted with R₁₂ wherein R₁₂ is NHR₁₃ by standard methods such as treatment with an appropriate acid chloride (R₁₄COCl), chloroformate (ClCO₂R₁₇) or sulphonyl chloride (R₁₇SO₂Cl) in the presence of a suitable base such as triethyl amine.

Compounds of formula (1) where R₃ is alkyl substituted with R₁₂ wherein R₁₂ is NR₁₃CONR₁₄R₁₅ may be prepared from compounds of formula (1) where R₃ is alkyl substituted with R₁₂ wherein R₁₂ is NHR₁₃ by standard methods such as treatment with an appropriate isocyanate (R₁₄NCO or R₁₅NCO) or carbamoyl chloride (R₁₄R₁₅NCOCl).

Compounds of formula (1) where R₃ is alkyl substituted with R₁₂ wherein R₁₂ is NHR₁₃ may be prepared from compounds of formula (1) where R₃ is alkyl substituted with R₁₂ wherein R₁₂ is NH₂ by standard methods such as alkylation or reductive alkylation.

Compounds of formula (1) where R₃ is alkyl substituted with R₁₂ wherein R₁₂ is NH₂ may be prepared from compounds of formula (1) where R₃ is alkyl substituted with R₁₂ wherein R₁₂ is phthalimide by standard methods such as treatment with hydrazine. Compounds of formula (1) where R₃ is alkyl substituted with R₁₂ wherein R₁₂ is phthalimide may be prepared from compounds of formula (2) by standard methods such as treatment with an appropriate substituted alkyl halide in the presence of a suitable base such as sodium hydride.

Compounds of formula (1) where R₃ is an ethyl group substituted in the D-position with an electron withdrawing group such as an ester, amide, ketone or nitrile group may be prepared from compounds of formula (2) by standard methods such as Michael addition with a suitable α,β-unsaturated ester, amide, ketone or nitrile. It will be appreciated by those skilled in the art that selection of an α,β-unsaturated ester, amide, ketone or nitrile which contained additional substituents would lead in an analogous way to compounds of formula (1) where R₃ is an ethyl group substituted in the β-position with an ester, amide, ketone or nitrile and additionally substituted elsewhere.

Compounds of formula (1) where R₃ is CONR₉R₁₀ or CONR₈NR₉R₁₀ may be prepared from compounds of formula (2) by standard methods such as treatment with an appropriate isocyanate (R₉NCO or R₁₀NCO) or carbamoyl chloride (R₉R₁₀NCOCl, or R₈R₉NR₁₀NCOCl).

Compounds of formula (1) where R₃ is COR₈, CO₂R₁₁ or SO₂R₁₁ may be prepared from compounds of formula (2) by standard methods such as treatment with an appropriate acid chloride (R₈COCl), chloroformate (ClCO₂R₁₁) or sulphonyl chloride (R₁₁SO₂Cl) in the presence of a suitable base such as triethylamine.

Compounds of formula (2) where R₁ is alkoxy, aryloxy, alkylthio, arylthio, CN or NR₅R₆ may be prepared from compounds of formula (3) by standard methods such as nucleophilic displacement using an appropriate nucleophilic reagent such as an alcohol, thiol, cyanide or amine (HNR₅R₆) in the presence of a suitable base if required.

Compounds of formula (3) may be prepared from the commercially available chloro compound of formula (4) by standard methods such as aryl or heteroaryl coupling reactions. Suitable aryl or heteroaryl coupling reactions would include reaction with an appropriate aryl or heteroaryl trialkylstannane derivative, an aryl or heteroarylboronic acid or boronic ester derivative, or an aryl or heteroarylzinc halide derivative in the presence of a suitable catalyst such as a palladium complex.

Compounds of formula (1) where R₁ is NR₄CONR₅R₆, wherein R₄ is H, may be prepared from compounds of formula (1) where R₁ is NH₂, by standard methods such as treatment with an appropriate isocyanate (R₅NCO or R₆NCO) or carbamoyl chloride (R₅R₆NCOCl).

Compounds of formula (1) where R₁ is NR₄CONR₅R₆, wherein R₄ is alkyl or aryl, may be prepared from compounds of formula (1) where R₁ is NR₅R₆, wherein one of R₅ and R₆ is alkyl or aryl and the other is H, by standard methods as described above.

Compounds of formula (1) where R₁ is NR₄COR₅, NR₄CO₂R₇ or NR₄SO₂R₇, wherein R₄ is H, may be prepared from compounds of formula (1) where R₁ is NH₂ by standard methods such as treatment with an appropriate acid chloride (R₅COCl), chloroformate (ClCO₂R₇) or sulphonyl chloride (R₇SO₂Cl) in the presence of a suitable base. Compounds of formula (1) where R₁ is NR₄COR₅, NR₄CO₂R₇ or NR₄SO₂R₇, wherein R₄ is alkyl or aryl, may be prepared from compounds of formula (1) where R₁ is NR₅R₆, wherein one of R₅ and R₆ is alkyl or aryl and the other is H, as described above.

Compounds of formula (1) where R₁ is NH₂ may be prepared from compounds of formula (1) where R₁ is NR₅R₆, wherein one of R₅ and R₆ is a protecting group and the other is H by standard methods such as treatment with TFA or Amberlyst-15. Suitable protecting groups would include 3,4-dimethoxybenzyl and THP.

Alternatively it may be advantageous to prepare compounds of formula (1) from compounds of formula (5) by standard methods such as nucleophilic displacement reactions as described above. Compounds of formula (5) are prepared either from compounds of formula (3) or from compounds of formula (6) by standard methods as described above. Compounds of formula (6) are prepared from compounds of formula (4) by standard methods as described above.

Compounds of formula (1) where R₁ is alkyl may be prepared from compounds of formula (5) by standard methods such as reaction with a suitable reagent such as a trialkylaluminium reagent preferably in the presence of a suitable catalyst such as a palladium catalyst.

Compounds of formula (1) where R₁ is aryl may be prepared from compounds of formula (5) by standard methods such as aryl coupling reaction as described above.

Alternatively compounds of formula (1) where R₁ is NH₂ may be prepared by standard methods such as those illustrated in Reaction Scheme 2.

Compounds of formula (7) are prepared from compounds of formula (8) by standard methods such as those described above. Alternatively compounds of formula (7) are prepared from compounds of formula (10) by standard methods such as those described above. Compounds of formula (8) and formula (10) are prepared from the commercially available compound of formula (9) by standard methods such as those described above. In certain cases it may be advantageous to prepare compounds of formula (8) from compounds of formula (11) where P is a protecting group, for example THP. Compounds of formula (11) may be transformed into compounds of formula (8) by standard methods such as aryl coupling reactions as described above followed by removal of the protecting groups by standard methods such as treatment with Amberlyst-15. Compounds of formula (11) are either known in the literature or may be prepared by methods analogous to those reported in the literature.

Alternatively compounds of formula (I) where R₁ is alkyl or aryl are prepared by standard methods such as those illustrated in Reaction Scheme 3.

Compounds of formula (1) where R₁ is alkyl or aryl are prepared from compounds of formula (2) where R₁ is alkyl or aryl by standard methods such as those described above. Alternatively compounds of formula (1) where R₁ is alkyl or aryl are prepared from compounds of formula (12) where R₁ is alkyl or aryl by standard methods such as those described above. Compounds of formula (2) where R₁ is alkyl or aryl and compounds of formula (12) where R₁ is alkyl or aryl are prepared from compounds of formula. (13) by standard methods such as those described above. Compounds of formula (13) where R₁ is alkyl or aryl are either known in the literature or may be prepared by methods analogous to those reported in the literature.

In the compounds of the present invention, where any of the groups R₁ to R₁₁ is an alkyl group or aryl group or where any of the groups R₁ to R₁₁ contains an alkyl or aryl substituent, the alkyl or aryl group may also be substituted. It will be appreciated by those skilled in the art that certain substituents on the alkyl or aryl groups mentioned above may be introduced directly as an integral part of the substituent R₁ to R₁₁ by using the synthetic methods described above. In other cases it may be advantageous to introduce certain substituents on the alkyl or aryl groups mentioned above by chemical transformation of other substituent groups. For example where the alkyl or aryl group mentioned above contains an amino substituent this may be converted to an alkylamino or dialkylamino group by standard methods such as alkylation or reductive alkylation, or to an amide, carbamate, urea or sulphonamide by standard methods such as those described above. Additionally, for example, where the alkyl or aryl group mentioned above contains a carboxylic ester substituent this may be converted to an amide or hydrazide derivative by standard methods such as reaction with an amine or hydrazine directly or in the presence of a catalyst such as Me₃Al if required. It will be appreciated by those skilled in the art that substituents such as an amino group or a carboxylic ester group may also be transformed by standard methods to a wide range of additional substituent groups.

According to a further aspect of the invention, there is provided a pharmaceutical composition comprising a compound of formula (I) in combination with a pharmaceutically acceptable carrier or excipient and a method of making such a composition comprising combining a compound of the present invention with a pharmaceutically acceptable carrier or excipient.

The pharmaceutical compositions employed in the present invention comprise a compound of formula (I), or pharmaceutically acceptable salts or prodrugs thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients known to those skilled in the art. The term, “pharmaceutically acceptable salts”, refers to salts prepared from pharmaceutically acceptable non-toxic acids including inorganic acids and organic acids.

Where the compounds of formula (I) are basic, salts may be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, oxalic, p-toluenesulfonic and the like. Particularly preferred are hydrochloric, hydrobromic, phosphoric, and sulfuric acids, and most particularly preferred is the hydrochloride salt.

Any suitable route of administration may be employed for providing the patient with an effective dosage of a compound of formula (I). For example, oral, rectal, parenteral (intravenous, intramuscular), transdermal, subcutaneous, and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, patches, and the like. The most suitable route in any given case will depend on the severity of the condition being treated. The most preferred route of administration is the oral route. The compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

In practical use, the compounds of formula (I) can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g. oral or parenteral (e.g. intravenous). In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed as carriers, such as, for example, water, glycols, oils, alcohols, flavouring agents, preservatives, colouring agents, and the like in the case of oral liquid preparations (such as suspensions, solutions and elixirs) or aerosols; or carriers such as starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used in the case of oral solid preparations such as, for example, powders, capsules, and tablets, with the solid oral preparations being preferred over the liquid preparations. The most preferred solid oral preparation is tablets.

Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are employed. If desired, tablets may be coated by standard aqueous or non-aqueous techniques.

In addition to the common dosage forms set out above, the compounds of formula (I) may also be administered by controlled release means and/or delivery devices such as those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 3,630,200; 4,008,719; 4,687,660; and 4,769,027, the disclosures of which are hereby incorporated by reference.

Pharmaceutical compositions suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets, or aerosol sprays each containing a predetermined amount of the active ingredient as a powder or granules, a solution or a suspension in an aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion. Such compositions may be prepared by any of the methods of pharmacy, but all methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.

For example, a tablet may be prepared by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, a lubricant, an inert diluent, and/or a surface active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

The invention is further defined by reference to the following examples. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practised without departing from the purpose and interest of this invention.

EXAMPLES Synthetic Examples

The invention is illustrated with reference to the Examples set out in Table 1. The syntheses of the Examples are performed using the general Synthetic Methods set out hereinafter. The Method used for a given Example is noted in parentheses in column 1 of Table 1. Table 2 includes the analytical data for the compounds. TABLE 1 Ex- ample Structure Compound Name 1 (A)

2-Chloro-6-(2-furyl)-9-(2-tri- methylsilylethoxymethyl)-9H-purine 2 (B)

N,N-Dimethyl-6-(2-furyl)-9-(2-tri- methylsilylethoxymethyl)-9H-purine-2-amine 3 (C)

N,N-Dimethyl-6-(2-furyl)-1H-purine-2-amine 4 (B)

6-(2-Furyl)-N-(2-hydroxyethyl)-9-(2-tri- methylsilylethoxymethyl)-9H-purine-2-amine 5 (C)

N-(2-Hydroxyethyl)-6-(2-furyl)-1H-purine-2-amine 6 (S)

2-Chloro-9-cyclopentyl-6-(2-furyl)-9H-purine 7 (A)

tert-Butyl 2-chloro-6-(2-furyl)-9H-purine-9-carboxylate 8 (A)

2-Chloro-6-(2-furyl)-1H-purine 9 (B)

(2R)-1-(6-(2-Furyl)-1H-purine-2-yl)-2-pyrrolidinemethanol 10 (B)

N-(3,4-Dimethoxybenzyl)-6-(2-furyl)-1H-purine-2-amine 11 (D)

6-(2-Furyl)-1H-purine-2-amine 12 (E)

tert-Butyl 6-(2-furyl)-2-methylthio-9H-purine-9-carboxylate 13 (F)

6-(2-Furyl)-2-methylthio-1H-purine 14 (A)

tert-Butyl 2-amino-6-(2-furyl)-9H-purine-9-carboxylate 15 (B)

N-Allyl-6-(2-furyl)-9-(2-tri- methylsilylethoxymethyl)-9H-purine-2-amine 16 (B)

6-(2-Furyl)-N-methyl-9-(2-tri- methylsilylethoxymethyl)-9H-purine-2-amine 17 (C)

N-Allyl-6-(2-furyl)-1H-purine-2-amine 18 (C)

6-(2-Furyl)-N-methyl-1H-purine-2-amine 19 (A)

2-Amino-N-cylcohexyl-6-(2-furyl)-9H-purine-9-carboxamide 20 (A)

2-Methylpropyl 2-amino-6-(2-furyl)-9H-purine-9-carboxylate 21 (A)

2-Amino-N-tert-butyl-6-(2-furyl)-9H-purine-9-carboxamide 22 (A)

Phenyl 2-amino-6-(2-furyl)-9H-purine-9-carboxylate 23 (A)

N-(6-(2-Furyl)-1H-purine-2-yl)-N′-phenylurea 24 (A)

2-Amino-N-ethyl-6-(2-furyl)-9H-purine-9-carboxamide 25 (A)

2-Amino-6-(2-furyl)-N-phenyl-9H-purine-9-carboxamide 26 (G)

2-Amino-N-benzyl-6-(2-furyl)-9H-purine-9-carboxamide 27 (H)

9-(4-tert-Butylphenylsulphonyl)-6-(2-furyl)-9H-pur- ine-2-amine 28 (H)

9-Cyclohexylcarbonyl-6-(2-furyl)-9H-purine-2-amine 29 (I)

6-(2-Furyl)-9-(1-pyrrolidinylcarbonyl)-9H-purine-2-amine 30 (G)

2-Amino-6-(2-furyl)-N-isopropyl-9H-purine-9-carboxamide 31 (A)

2-Chloro-N-cyclohexyl-6-(2-furyl)-9H-purine-9-carboxamide 33 (H)

6-(2-Furyl)-9-(3-methylbutyryl)-9H-purine-2-amine 34 (H)

9-Acetyl-6-(2-furyl)-9H-purine-2-amine 35 (G)

N-Benzyl-6-(2-furyl)-2-methylthio-9H-purine-9-carboxamide 36 (G)

2-Amino-N-n-butyl-6-(2-furyl)-9H-purine-9-carboxamide 37 (G)

2-Amino-6-(2-furyl)-N-(4-methoxybenzyl)-9H-pur- ine-9-carboxamide 38 (G)

2-Amino-6-(2-furyl)-N-(4-methylbenzyl)-9H-purine-9-carboxamide 39 (G)

2-Amino-N-(2-chlorobenzyl)-6-(2-furyl)-9H-purine-9-carboxamide 40 (G)

2-Amino-6-(2-furyl)-N-(1-naphthyl)-9H-purine-9-carboxamide 41 (G)

2-Amino-6-(2-furyl)-N-n-heptyl-9H-purine-9-carboxamide 42 (G)

2-Amino-6-(2-furyl)-N-(2-methylphenyl)-9H-purine-9-carboxamide 43 (G)

2-Amino-6-(2-furyl)-N-(3-methylphenyl)-9H-purine-9-carboxamide 44 (G)

2-Amino-N-(2-chlorophenyl)-6-(2-furyl)-9H-purine-9-carboxamide 45 (G)

(1S)-2-Amino-6-(2-furyl)-N-(1-phenylethyl)-9H-pur- ine-9-carboxamide 46 (G)

(1R)-2-Amino-6-(2-furyl)-N-(1-phenylethyl)-9H-pur- ine-9-carboxamide 47 (G)

2-Amino-6-(2-furyl)-N-(3-methylbenzyl)-9H-purine-9-carboxamide 48 (G)

2-Amino-6-(2-furyl)-N-(4-methylphenyl)-9H-purine-9-carboxamide 49 (G)

2-Amino-6-(2-furyl)-N-(2-methoxyphenyl)-9H-pur- ine-9-carboxamide 50 (G)

2-Amino-6-(2-furyl)-N-(4-methoxyphenyl)-9H-pur- ine-9-carboxamide 51 (G)

2-Amino-N-(4-chlorophenyl)-6-(2-furyl)-9H-purine-9-carboxamide 52 (G)

2-Amino-6-(2-furyl)-N-n-pentyl-9H-purine-9-carboxamide 53 (G)

2-Amino-N-n-dodecyl-6-(2-furyl)-9H-purine-9-carboxamide 54 (K)

9-(2-Cyclohexylethyl)-6-(2-furyl)-9H-purine-2-amine 55 (G)

N-Benzyl-2-dimethylamino-6-(2-furyl)-9H-purine-9-carboxamide 56 (H)

N,N-Dimethyl-6-(2-furyl)-9-(4-methyl- phenylsulphonyl)-9H-purine-2-amine 57 (K)

6-(2-Furyl)-9-(1-phenyl-1-propene-3-yl)-9H-purine-2-amine 58 (K)

9-(But-2-ene-4-yl)-6-(2-furyl)-9H-purine-2-amine 59 (K)

9-n-Butyl-6-(2-furyl)-9H-purine-2-amine 60 (K)

9-Cyclopentyl-6-(2-furyl)-9H-purine-2-amine 61 (K)

6-(2-Furyl)-9-isopropyl-9H-purine-2-amine 62 (K)

6-(2-Furyl)-9-(4-phenylbutyl)-9H-purine-2-amine 63 (K)

9-(2-Benzyloxyethyl)-6-(2-furyl)-9H-purine-2-amine 64 (K)

6-(2-Furyl)-9-(3-methylbutyl)-9H-purine-2-amine 65 (K)

6-(2-Furyl)-9-(2-methyl-2-buten-4-yl)-9H-purine-2-amine 66 (K)

9-Benzyl-6-(2-furyl)-9H-purine-2-amine 67 (K)

9-(4-Chlorobenzyl)-6-(2-furyl)-9H-purine-2-amine 68 (K)

6-(2-Furyl)-9-(3-phenylpropyl)-9H-purine-2-amine 69 (X)

Ethyl 2-amino-6-(2-furyl)-9H-purine-9-acetate 70 (L)

Isopropyl 2-dimethylamino-6-(2-furyl)-9H-purine-9-acetate 71 (B)

Ethyl 2-dimethylamino-6-(2-furyl)-9H-purine-9-acetate 72 (A)

Ethyl 2,6-bis(2-furyl)-9H-purine-9-acetate 73 (M)

2-Amino-6-(2-furyl)-9H-purine-9-acetic acid 74 (N)

6-(2-Furyl)-2-methoxy-9-(2-tri- methylsilylethoxymethyl)-9H-purine 75 (C)

6-(2-Furyl)-2-methoxy-1H-purine 76 (O)

6-(2-Thienyl)-1H-purine-2-amine 77 (G)

2-Amino-N-benzyl-6-(2-thienyl)-9H-purine-9-carboxamide 78 (A)

tert-Butyl 2-amino-6-(2-thienyl)-9H-purine-9-carboxylate 79 (G)

2-Amino-N-(4-fluorobenzyl)-6-(2-furyl)-9H-purine-9-carboxamide 80 (G)

2-Amino-N-(3,4-dichlorobenzyl)-6-(2-furyl)-9H-pur- ine-9-carboxamide 81 (K)

6-(2-Furyl)-9-(2-phenylethyl)-9H-purine-2-amine 82 (K)

9-(1-(4-Fluorophenyl)ethyl)-6-(2-furyl)-9H-purine-2-amine 83 (K)

6-(2-Furyl)-9-(4-isopropylbenzyl)-9H-purine-2-amine 84 (K)

9-(3,4-Difluorobenzyl)-6-(2-furyl)-9H-purine-2-amine 85 (P)

2-Amino-6-(2-furyl)-N-phenyl-9H-purine-9-acetamide 86 (Q)

2-Amino-N-benzyl-6-(2-furyl)-9H-purine-9-acetamide 87 (Q)

2-Amino-6-(2-furyl)-9H-purine-9-acetamide 88 (Q)

6-(2-Furyl)-9-(2-oxo-2-(1-pyrrolidinyl)ethyl)-9H-pur- ine-2-amine 89 (Q)

2-Amino-6-(2-furyl)-N-methyl-9H-purine-9-acetamide 90 (R)

6-(5-Methyl-[1,2,4]-oxadiazol-3-yl)-1H-purine-2-amine 91 (G)

2-Amino-N-benzyl-6-(5-methyl-[1,2,4]-oxadiazol-3-yl)-9H-pur- ine-9-carboxamide 92 (G)

2-Amino-6-(2-furyl)-N-(2-phenylethyl)-9H-purine-9-carboxamide 93 (G)

2-Amino-N-(2,4-dichlorobenzyl)-6-(2-furyl)-9H-pur- ine-9-carboxamide 94 (G)

(1RS)-2-Amino-6-(2-furyl)-N-(1-(1-naphthyl)ethyl)-9H-pur- ine-9-carboxamide 95 (G)

2-Amino-6-(2-furyl)-N-(2-(3-isopropenylphenyl)-2-pro- pyl)-9H-purine-9-carboxamide 96 (Q)

2-Amino-6-(2-furyl)-N-(2-hydroxyethyl)-9H-purine-9-acetamide 97 (Q)

6-(2-Furyl)-9-(2-oxo-2-(4-methyl-1-pipe- razinyl)ethyl)-9H-purine-2-amine 98 (G)

2-Amino-N-(2-chloroethyl)-6-(2-furyl)-9H-purine-9-carboxamide 99 (G)

2-Amino-N-(3-chloropropyl)-6-(2-furyl)-9H-purine-9-carboxamide 100 (G)

Ethyl 3-(2-Amino-6-(2-furyl)-9H-purine-9-yl)carbonyl- aminopropionate 101 (G)

Ethyl 2-(2-Amino-6-(2-furyl)-9H-purine-9-yl)carbonyl- amino-3-phenylpropionate 102 (S)

6-(2-Furyl)-9-(2-(2-pyridyl)ethyl)-9H-purine-2-amine 103 (S)

6-(2-Furyl)-9-(2-(1-piperazinyl)ethyl)-9H-purine-2-amine 104 (S)

6-(2-Furyl)-9-(2-(1-piperidinyl)ethyl)-9H-purine-2-amine 105 (S)

6-(2-Furyl)-9-(2-(1-pyrrolidinyl)ethyl)-9H-purine-2-amine 106 (T)

Benzyl 2-amino-6-(2-furyl)-9H-purine-9-carboxylate 112 (G)

N-Benzyl-2-methoxy-6-(2-furyl)-9H-purine-9-carboxamide 113 (S)

9-(2-(4-Chlorophenyl)ethyl)-6-(2-furyl)-9H-purine-2-amine 114 (S)

9-(2-(4-Dimethylaminophenyl)ethyl)-6-(2-furyl)-9H-pur- ine-2-amine 115 (S)

6-(2-Furyl)-9-(2-phenoxyethyl)-9H-purine-2-amine 116 (S)

9-Cyclohexylmethyl-6-(2-furyl)-9H-purine-2-amine 117 (S)

9-(3-Cyclohexylpropyl)-6-(2-furyl)-9H-purine-2-amine 118 (I)

2-Amino-N-benzyl-6-(2-furyl)-N-methyl-9H-purine-9-carboxamide 119 (Q)

2-Amino-6-(2-furyl)-N-(2-pyridylmethyl)-9H-pur- ine-9-acetamide 120 (O)

6-(Benzofuran-2-yl)-1H-purine-2-amine 122 (Q)

2-Amino-6-(2-furyl)-N-(2-pyridyl)-9H-purine-9-acetamide 123 (Q)

2-Amino-6-(2-furyl)-N-(2-phenylethyl)-9H-purine-9-acetamide 124 (Q)

2-Amino-6-(2-furyl)-N-n-propyl-9H-purine-9-acetamide 125 (S)

9-(3-Chlorobenzyl)-6-(2-furyl)-9H-purine-2-amine 126 (S)

6-(2-Furyl)-9-(3-methylbenzyl)-9H-purine-2-amine 127 (S)

6-(2-Furyl)-9-(4-methylbenzyl)-9H-purine-2-amine 128 (G)

2-Amino-6-(benzofuran-2-yl)-N-benzyl-9H-purine-9-carboxamide 129 (O)

6-(5-Chloro-2-thienyl)-1H-purine-2-amine 130 (G)

2-Amino-N-benzyl-6-(5-chloro-2-thienyl)-9H-pur- ine-9-carboxamide 131 (I)

6-(2-Furyl)-9-(1,2,3,4-tetrahydroisoquinolin-2-yl- carbonyl)-9H-purine-2-amine 132 (I)

6-(2-Furyl)-9-(1-indolinylcarbonyl)-9H-purine-2-amine 133 (A)

6-(1-Methyl-1H-pyrrol-2-yl)-1H-purine-2-amine 134 (G)

2-Amino-N-benzyl-6-(1-methyl-1H-pyrrol-2-yl)-9H-pur- ine-9-carboxamide 137 (Y)

6-(5-Thiazolyl)-1H-purine-2-amine 139 (G)

2-Amino-N-benzyl-6-(5-thiazolyl)-9H-purine-9-carboxamide 140 (Q)

2-Amino-6-(2-furyl)-N-(2-methylphenyl)-9H-purine-9-acetamide 141 (Q)

2-Amino-N-(3-chlorophenyl)-6-(2-furyl)-9H-purine-9-acetamide 142 (Q)

2-Amino-6-(2-furyl)-N-(4-pyridyl)-9H-purine-9-acetamide 143 (Q)

2-Amino-6-(2-furyl)-N-(3-pyridyl)-9H-purine-9-acetamide 144 (Q)

2-Amino-N-(4-chlorobenzyl)-6-(2-furyl)-9H-purine-9-acetamide 145 (Q)

2-Amino-N-benzyl-6-(2-furyl)-N-methyl-9H-purine-9-acetamide 146 (S)

6-(2-Furyl)-9-(2-(4-pyridyl)ethyl)-9H-purine-2-amine 147 (S)

6-(2-Furyl)-9-(2-(4-morpholinyl)ethyl)-9H-purine-2-amine 148 (S)

6-(2-Furyl)-9-(3-pyridylmethyl)-9H-purine-2-amine 150 (A)

6-(3-Methyl-2-thienyl)-1H-purine-2-amine 151 (AA)

Methyl 3-(2-amino-6-(2-furyl)-9H-purine-9-yl)pro- pionate 152 (M)

3-(2-Amino-6-(2-furyl)-9H-purine-9-yl)propionic acid 153 (AB)

6-(2-Furyl)-2-methyl-1H-purine 154 (G)

N-Benzyl-6-(2-furyl)-2-methyl-9H-purine-9-carboxamide 155 (H)

6-(2-Furyl)-9-isopropylsulphonyl-9H-purine-2-amine 156 (AC)

2-Chloro-6-(2-furyl)-9-(4-methylbenzyl)-9H-purine 157 (AC)

9-(2-Fluorobenzyl)-6-(2-furyl)-9H-purine-2-amine 158 (AC)

6-(2-Furyl)-9-(3-nitrobenzyl)-9H-purine-2-amine 159 (AC)

6-(2-Furyl)-9-(4-trifluoromethylbenzyl)-9H-purine-2-amine 160 (H)

6-(2-Furyl)-9-(3-nitrophenyl)sulphonyl-9H-purine-2-amine 161 (H)

9-(2-Bromophenyl)sulphonyl-6-(2-furyl)-9H-purine-2-amine 162 (H)

9-(4-Bromophenyl)sulphonyl-6-(2-furyl)-9H-purine-2-amine 163 (H)

9-(4-Fluorophenyl)sulphonyl-6-(2-furyl)-9H-purine-2-amine 164 (H)

6-(2-Furyl)-9-methanesulphonyl-9H-purine-2-amine 165 (H)

9-Butanesulphonyl-6-(2-furyl)-9H-purine-2-amine 166 (H)

6-(2-Furyl)-9-(8-quinolinesulphonyl)-9H-purine-2-amine 167 (H)

9-(3,5-Dimethylisoxazole-4-yl)sulphonyl-6-(2-fur- yl)-9H-purine-2-amine 168 (H)

6-(2-Furyl)-9-(5-(2-pyridyl)-2-thienyl)sulphonyl-9H-pur- ine-2-amine 169 (Q)

2-Amino-6-(2-furyl)-N-(4-methoxy-2-meth- ylphenyl)-9H-purine-9-acetamide 170 (Q)

2-Amino-N-(2,4-dimethylphenyl)-6-(2-furyl)-9H-pur- ine-9-acetamide 171 (I)

N-Benzyl-N,2-dimethyl-6-(2-furyl)-9H-purine-9-carboxamide 172 (AC)

6-(2-Furyl)-9-(4-nitrobenzyl)-9H-purine-2-amine 173 (AH)

6-(2-Furyl)-9-(4-methylbenzyl)-9H-purine-2-carbonitrile 174 (X)

6-(2-Furyl)-9-(2-phthalimidoethyl)-9H-purine-2-amine 175 (Q)

2-Amino-N-(4-chlorophenyl)-6-(2-furyl)-9H-purine-9-acetamide 176 (Q)

2-Amino-N-(3,4-dichlorophenyl)-6-(2-furyl)-9H-pur- ine-9-acetamide 177 (AC)

9-(3-Cyanobenzyl)-6-(2-furyl)-9H-purine-2-amine 178 (AC)

9-(2-Chlorobenzyl)-6-(2-furyl)-9H-purine-2-amine 179 (H)

N-(5-(2-Amino-6-(2-furyl)-9H-purine-9-yl- sulphonyl)-2-thienylmethyl)-4-chlorobenzamide 180 (H)

9-(2,1,3-Benzoxadiazol-4-yl)sulphonyl-6-(2-furyl)-9H-pur- ine-2-amine 181 (H)

Mehtyl 3-(2-amino-6-(2-furyl)-9H-purine-9-sul- phonyl)thiophene-2-carboxylate 182 (H)

6-(2-Furyl)-9-(5-(isoxazol-3-yl)-2-thienyl)sulphonyl-9H-pur- ine-2-amine 183 (H)

6-(2-Furyl)-9-(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)sul- phonyl-9H-purine-2-amine 184 (H)

9-(4-Acetylphenylsulphonyl)-6-(2-furyl)-9H-purine-2-amine 185 (H)

6-(2-Furyl)-9-(2-phenylethenyl)sulphonyl-9H-pur- ine-2-amine 186 (H)

9-Ethanesulphonyl-6-(2-furyl)-9H-purine-2-amine 187 (S)

6-(2-Furyl)-9-(2-pyridylmethyl)-9H-purine-2-amine 188 (S)

6-(2-Furyl)-9-(4-pyridylmethyl)-9H-purine-2-amine 189 (S)

6-(2-Furyl)-9-(3-(3-pyridyl)propyl)-9H-purine-2-amine 190 (S)

6-(2-Furyl)-9-(3-(4-pyridyl)propyl)-9H-purine-2-amine 191 (G)

2-Amino-N-(1-(4-bromophenyl)ethyl)-6-(2-furyl)-9H-pur- ine-9-carboxamide 192 (AD)

9-(3-Aminobenzyl)-6-(2-furyl)-9H-purine-2-amine 193 (AC)

Methyl 3-(2-amino-6-(2-furyl)-9H-purine-9-yl- methyl)benzoate 194 (AC)

9-(4-Cyanobenzyl)-6-(2-furyl)-9H-purine-2-amine 195 (Y)

6-(5-Methyl-2-furyl)-1H-purine-2-amine 196 (H)

9-n-Decanesulphonyl-6-(2-furyl)-9H-purine-2-amine 197 (AC)

6-(2-Furyl)-9-(2-nitrobenzyl)-9H-purine-2-amine 198 (AC)

6-(2-Furyl)-9-(3-methoxybenzyl)-9H-purine-2-amine 199 (M)

3-(2-Amino-6-(2-furyl)-9H-purine-9-yl- methyl)benzoic acid 200 (B)

N,N-Dimethyl-6-(2-furyl)-9-(4-methylbenzyl)-9H-pur- ine-2-amine 201 (G)

2-Amino-6-(2-furyl)-N-(2-furylmethyl)-9H-purine-9-carboxamide 202 (G)

2-Amino-6-(2-furyl)-N-(2-thienylmethyl)-9H-pur- ine-9-carboxamide 203 (AC)

9-(3-Fluorobenzyl)-6-(2-furyl)-9H-purine-2-amine 204 (G)

2-Amino-N-benzyl-6-(5-methyl-2-furyl)-9H-purine-9-car- boxamide 205 (AF)

9-(3-Acetamidobenzyl)-6-(2-furyl)-9H-purine-2-amine 206 (AC)

6-(2-Furyl)-9-(4-methanesulphonylbenzyl)-9H-pur- ine-2-amine 207 (AD)

9-(2-Aminobenzyl)-6-(2-furyl)-9H-purine-2-amine 208 (AC)

9-(4-Methylbenzyl)-6-(5-methyl-2-furyl)-9H-purine-2-amine 209 (Y)

6-(1-Methyl-1H-imidazol-5-yl)-1H-purine-2-amine 210 (AF)

6-(2-Furyl)-9-(2-methanesulphonylaminobenzyl)-9H-pur- ine-2-amine 211 (AC)

9-(2,6-Difluorobenzyl)-6-(2-furyl)-9H-purine-2-amine 212 (S)

6-(2-Furyl)-9-(6-methyl-2-pyridyl)methyl-9H-pur- ine-2-amine 213 (S)

6-(2-Furyl)-9-(3-furylmethyl)-9H-purine-2-amine 214 (H)

9-Benzylsulphonyl-6-(2-furyl)-9H-purine-2-amine 215 (AC)

Methyl 4-(2-amino-6-(2-furyl)-9H-purine-9-yl- methyl)benzoate 216 (M)

4-(2-Amino-6-(2-furyl)-9H-purine-9-yl- methyl)benzoic acid 217 (AF)

6-(2-Furyl)-9-(3-methanesulphonylaminobenzyl)-9H-pur- ine-2-amine 218 (Q)

2-Amino-6-(2-furyl)-N-(2-furylmethyl)-9H-purine-9-acetamide 219 (AC)

9-(3,5-Dimethoxybenzyl)-6-(2-furyl)-9H-purine-2-amine 220 (AF)

9-(2-Acetamidobenzyl)-6-(2-furyl)-9H-purine-2-amine 221 (AG)

6-(2-Furyl)-9-(3-hydroxybenzyl)-9H-purine-2-amine 222 (S)

N-(2-(2-Amino-6-(2-furyl)-9H-purine-9-yl)ethyl)-4-py- ridinecarboxamide 223 (S)

6-(2-Furyl)-9-(3-thienylmethyl)-9H-purine-2-amine 224 (S)

9-(1-Benzyl-1H-imidazol-2-ylmethyl)-6-(2-furyl)-9H-pur- ine-2-amine 225 (AD)

9-(4-Aminobenzyl)-6-(2-furyl)-9H-purine-2-amine 226 (P)

3-(2-Amino-6-(2-furyl)-9H-purine-9-ylmethyl)-N-benzyl- benzamide 227 (P)

4-(2-Amino-6-(2-furyl)-9H-purine-9-ylmethyl)-N-benzyl- benzamide 228 (H)

6-(2-Furyl)-9-(4-methylphenylsulphonyl)-9H-purine-2-amine 229 (AC)

9-(3,5-Dimethylisoxazol-4-ylmethyl)-6-(2-furyl)-9H-pur- ine-2-amine 230 (P)

3-(2-Amino-6-(2-furyl)-9H-purine-9-ylmethyl)-N,N-di- methylbenzamide 231 (Q)

2-Amino-6-(2-furyl)-N-(3-methoxyphenyl)-9H-pur- ine-9-acetamide 232 (AF)

6-(2-Furyl)-9-(4-methanesulphonylaminobenzyl)-9H-pur- ine-2-amine 233 (P)

4-(2-Amino-6-(2-furyl)-9H-purine-9-ylmethyl)-N,N-di- methylbenzamide 234 (AF)

N-(2-(2-Amino-6-(2-furyl)-9H-purine-9-yl- methyl)phenyl)cyclopropanecarboxamide 235 (AF)

6-(2-Furyl)-9-(2-(1-methyl-1H-imidazol-4-yl- sulphonylamino)benzyl)-9H-purine-2-amine 236 (Q)

2-Amino-6-(2-furyl)-N-(2-methoxybenzyl)-9H-pur- ine-9-acetamide 237 (Q)

2-Amino-N-(2-fluorobenzyl)-6-(2-furyl)-9H-purine-9-acetamide 238 (AF)

6-(2-Furyl)-9-(2-(2-thienylsulphonylamino)benzyl)-9H-pur- ine-2-amine 239 (AF)

6-(2-Furyl)-9-(2-(3,5-dimethylisoxazol-4-yl- sulphonylamino)benzyl)-9H-purine-2-amine 240 (AC)

9-(5-Chloro-2-thienylmethyl)-6-(2-furyl)-9H-purine-2-amine 241 (Z)

6-(5-Methyl-2-pyridinyl)-1H-purine-2-amine 242 (AF)

N-(6-(2-Furyl)-9-(2-(2-methylpropanamido)benzyl)-9H-pur- ine-2-yl)-2-methylpropanamide 243 (AC)

9-(2-Fluorobenzyl)-6-(5-methyl-2-pyridinyl)-9H-pur- ine-2-amine 244 (AJ)

9-(2-Fluorobenzyl)-6-(4-methyl-2-thiazolyl)-9H-pur- ine-2-amine 245 (AK)

2-Amino-N-benzyl-6-(2-furyl)-9H-purine-9-acetimid- amide 246 (Q)

2-Amino-6-(2-furyl)-N-(1-methylpropyl)-9H-purine-9-acetamide 247 (Q)

2-Amino-N-ethyl-6-(2-furyl)-9H-purine-9-acetamide 248 (Q)

N-Allyl-2-amino-6-(2-furyl)-9H-purine-9-acetamide 249 (Q)

2-Amino-N-(3,4-difluorophenyl)-6-(2-furyl)-9H-pur- ine-9-acetamide 250 (AF)

6-(2-Furyl)-9-(3-(3,5-dimethylisoxazol-4-yl- sulphonylamino)benzyl)-9H-purine-2-amine 251 (AL)

(2S)-9-(2-Amino-1-propyl)-6-(2-furyl)-9H-purine-2-amine 252 (Q)

2-Amino-N-(2-dimethylaminoethyl)-6-(2-furyl)-9H-pur- ine-9-acetamide 253 (AC)

9-(4-Fluorobenzyl)-6-(2-furyl)-9H-purine-2-amine 254 (AL)

(2R)-9-(2-Amino-1-propyl)-6-(2-furyl)-9H-purine-2-amine 255 (X)

9-(2-(Butoxycarbonylamino)ethyl)-6-(2-furyl)-9H-pur- ine-2-amine 256 (AC)

N,9-Bis(4-methylbenzyl)-6-(2-furyl)-9H-purine-2-amine 257 (F)

9-(2-Aminoethyl)-6-(2-furyl)-9H-purine-2-amine 258 (AC)

6-(2-Furyl)-N,N,9-tris(4-methylbenzyl)-9H-purine-2-amine 259 (AC)

9-(2-Fluoro-5-nitrobenzyl)-6-(2-furyl)-9H-purine-2-amine 260 (AG)

6-(2-Furyl)-9-(4-hydroxybenzyl)-9H-purine-2-amine 261 (AC)

6-(2-Furyl)-9-(4-methoxybenzyl)-9H-purine-2-amine 262 (AM)

9-(2-Fluorobenzyl)-6-(1H-pyrazol-3-yl)-9H-purine-2-amine 263 (AM)

9-(2-Fluorobenzyl)-6-(1H-triazol-3-yl)-9H-purine-2-amine 264 (AM)

9-(3-Aminobenzyl)-6-(1H-pyrazol-3-yl)-9H-purine-2-amine 265 (AO)

9-(3-Aminobenzyl)-6-(5-methyl-1H-pyrazol-3-yl)-1H-pur- ine-2-amine 266 (AC)

9-(3-Methoxybenzyl)-6-(5-methyl-2-furyl)-9H-pur- ine-2-amine 267 (AC)

9-(2-Fluorobenzyl)-6-(thiazol-5-yl)-9H-purine-2-amine 268 (AC)

9-(6-Allyloxymethyl-2-pyridyl)-6-(2-furyl)-9H-pur- ine-2-amine 269 (AC)

9-(3-Methyl-4-nitrobenzyl)-6-(2-furyl)-9H-purine-2-amine 270 (AC)

tert-butyl 4-(2-amino-6-(2-furyl)-1H-purine-9-yl- methyl)indole-1-carboxylate 271 (AQ)

6-(2-Furyl)-9-(4-indolylmethyl)-9H-purine-2-amine 272 (AQ)

6-(2-Furyl)-9-(5-indolylmethyl)-9H-purine-2-amine 273 (AC)

tert-butyl 5-(2-amino-6-(2-furyl)-1H-purine-9-yl- methyl)indole-1-carboxylate Method A

2-Chloro-6-(2-furyl)-9-(2-trimethylsilylethoxymethyl)-9H-purine (Example 1)

A solution of 2,6-dichloro-9-(2-trimethylsilylethoxymethyl)-9H-purine (957 mg, 3 mmol) in DMF (2.5 mL) was treated with PdCl₂(PPh₃)₂ (105 mg, 0.15 mmol) and 2-(tributylstannyl)furan (944 μL, 3 mmol), stirred at room temperature for 16 h, diluted with EtOAc, washed with water, dried (MgSO₄) and concentrated in vacuo, purified by chromatography [SiO₂; EtOAc:Heptane, (1:2)] and the resulting cream solid recrystallised (heptane) to give the title compound (738 mg, 70%) as a white solid.

Method B

N,N-Dimethyl-6-(2-furyl)-9-(2-trimethylsilylethoxymethyl)-9H-purine-2-amine (Example 2)

A solution of 2-chloro-6-(2-furyl)-9-(2-trimethylsilylethoxymethyl)-9H-purine (488 mg, 1.4 mmol) in isopropanol (5 mL) was treated with 40% dimethylamine in water (1 mL), refluxed for 2 h, concentrated in vacuo and purified by chromatography [SiO₂; EtOAc Heptane, (1:1)] to give the title compound (431 mg, 86%) as a white solid.

Method C

N,N-Dimethyl-6-(2-furyl)-1H-purine-2-amine (Example 3)

A solution of N,N-dimethyl-6-(2-furyl)-9-(2-trimethylsilylethoxymethyl)-9H-purine-2-amine (200 mg, 0.56 mmol) in TB (5 mL) was treated with tetra-n butylammonium fluoride (1-M in THF, 0.67 mL, 0.67 mmol), refluxed for 4 h, cooled, poured into water and extracted with EtOAc. The combined organic phase was dried (MgSO₄), concentrated in vacuo and purified by chromatography (SiO₂; EtOAc) to give the title compound (98 mg, 76%) as a pale yellow solid.

Method D

6-(2-Furyl)-1H-purine-2-amine (Example 11)

A solution of N-(3,4-dimethoxybenzyl)-6-(2-furyl)-1H-purine-2-amine (194 mg, 0.55 mmol) in TPA (1 mL) was heated at 60° C. for 30 min, poured into water, extracted with EtOAc and the combined organic phase was dried (MgSO₄), concentrated in vacuo and purified by chromatography (SiO₂; 5% MeOH in EtOAc). The resulting yellow solid was dissolved in MeOH, treated with HCl (1-M in Et₂O) and filtered to give the title compound (75 mg, 57%) as a yellow solid.

Method E

tert-Butyl 6-(2-furyl)-2-thiomethoxy-9H-purine-9-carboxylate (Example 12)

A solution of tert-butyl 2-chloro-6-(2-furyl)-9H-purine-9-carboxylate (320 mg, 1 mmol) in 1-methyl-2-pyrrolidinone (2 mL) was treated with NaSMe (140 mg, 2 mmol), heated at 110° C. for 48 h, cooled, poured into water, extracted with CHCl₃ and the combined organic phase dried (MgSO₄) and concentrated in vacuo. The resulting crude intermediate was dissolved in THF (2 mL), treated with di-tert-butyl dicarbonate (218 mg, 1 mmol), Et₃N (139 μL, 1 mmol) and a catalytic amount of DMAP, stirred for 1 h, poured into water, extracted with CHCl₃ and the combined organic phase dried MgSO₄), concentrated in vacuo and purified by chromatography [SiO₂; Eleptane:EtOAc (4:1)] to give the title compound (106 mg, 32%) as a cream solid.

Method F

6-(2-Furyl)-2-thiomethoxy-1H-purine (Example 13)

A solution of tert-butyl 6-(2-furyl)-2-thiomethoxy-9H-purine-9-carboxylate (75 mg, 0.23 mmol) in dioxan (0.5 mL) was treated with HCl in dioxan (4-M, 0.5 mL, 2 mmol), stirred at room temperature for 30 min, poured into sat. NaHCO₃, extracted with EtOAc and the combined organic phase dried (MgSO₄), concentrated in vacuo and the resulting cream solid triturated with EtOAc and filtered to give the title compound (46 mg, 86%) as a cream solid.

Method G

2-Amino-N-n-butyl-6-(2-furyl)-9H-purine-9-carboxamide (Example 36)

A solution of 6-(2-furyl)-1H-purine-2-amine (0.050 g, 0.25 mmol) and DMAP (5 mg, 0.03 mmol) in anhydrous DMF (1 mL) was treated with n-butylisocyanate (0.029 g, 0.30 mmol), shaken at 65° C. for 1 h, poured onto ice-cold water (10 mL), cooled at 0° C. for 15 min and the resulting precipitate filtered and dried in vacuo over P₂O₅ to give the title compound (74 mg, 100%) as a white solid.

Method H

9-(4-tert-Butylphenylsulphonyl)-(2-furyl)-9H-purine-2-amine (Example 27)

A solution of 6-(2-furyl)-1H-purine-2-amine (100 mg, 0.5 mmol) in THF (2 mL) and DMF (0.5 mL) was treated with 4-tert-butylbenzenesulphonyl chloride (116 mg, 0.5 mmol) and Et₃N (69 μL, 0.6 mmol), heated at 60° C. for 2 h, cooled, diluted with water and the resulting solid filtered and washed with EtOAc to give the title compound (106 mg, 53%) as a cream solid.

Method I

6-(2-Furyl)-9-(1-pyrrolidinylcarbonyl)-9H-purine-2-amine (Example 29)

A solution of pyrrolidine (50 mL, 0.6 mmol) in toluene (2 mL) was treated with a solution of phosgene in toluene (0.31 mL, 1.93-M, 0.6 mmol), heated at 80° C. for 30 mins, cooled and concentrated in vacuo. The residue was dissolved in THF (2 mL) and added to a solution of 6-(2-furyl)-1H-purine-2-amine (100 mg, 0.5 mmol) and Et₃N (83 mL, 0.6 mmol) in DMF (0.5 mL), stirred at 60° C. for 16 h, poured into water and extracted with EtOAc. The combined organic phase was dried (MgSO₄), concentrated in vacuo and the resulting solid triturated with EtOAc/heptane and filtered to give the title compound (92 mg, 62%) as a cream solid.

Method K

9-(2-Cyclohexylethyl)-6-(2-furyl)-9H-purine-2-amine (Example 54)

A solution of 6-(2-furyl)-1H-purine-2-amine (25 mg, 0.12 mmol) in anhydrous DMF (0.5 mL) and anhydrous THF (2 mL) was treated with triphenylphosphine polystyrene (65 mg, 0.25 mmol) and 2-cyclohexylethanol (35 mg, 0.25 mmol), shaken at room temperature for 10 min, treated with di-tert-butyl azodicarboxylate (0.058 g, 0.25 mmol), shaken at room temperature for 16 h, filtered and concentrated in vacuo. The resulting oil was dissolved in CH₂Cl₂ (2 mL) and TFA (1 mL), shaken for 2 h and concentrated in vacuo. The resulting oil was dissolved in CH₂Cl₂ (3 mL), shaken with 1-M aq HCl (1 mL) for 15 min and the organic phase concentrated in vacuo and purified by chromatography (SiO₂; EtOAc) to give the title compound (22 mg, 57%) as a yellow solid.

Method L

Isopropyl 2-dimethylamino-6-(2-furyl)-9H-purine-9-acetate (Example 70)

A solution of ethyl 2-chloro-6-(2-furyl)-9H-purine-9-acetate (100 mg, 0.33 mol) in isopropanol (1 mL) was treated with 40% dimethylamine in water, refluxed for 2 h, cooled, poured into water, extracted with EtOAc and the combined organic phase dried (MgSO₄), concentrated in vacuo and purified by chromatography [SiO₂; Heptane:EtOAc, (1:1)] to give the title compound (20 mg, 19%) as a white solid.

Method M

2-Amino-6-(2-furyl)-9H-purine-9-acetic acid (Example 73)

A solution of ethyl 2-amino-6-(2-furyl)-9H-purine-9-acetate (200 mg, 0.69 mmol) in MeOH (3 mL) was treated with aq NaOH (2-M, 0.5 mL, 1 mmol), refluxed for 10 min, cooled, diluted with water, acidified with aq HCl (1-M) and the resulting solid filtered, washed with water and dried to give the title compound (129 mg, 72%) as a yellow solid.

Method N

6-(2-Furyl)-2-methoxy-9-(2-trimethylsilylethoxymethyl)-9H-purine (Example 74)

A solution of 2-chloro-6-(2-furyl)-9-(2-trimethylsilylethoxymethyl)-9H-purine (0.35 g, 1.0 mmol) and sodium methoxide (60 mg, 1.1 mmol) in methanol (5 mL) was refluxed for 23 h, cooled, concentrated in vacuo and the resulting solid treated with water, acidified to pH 4 with acetic acid, extracted with EtOAc, dried (Na₂SO₄), concentrated in vacuo and purified by chromatography [SiO₂; EtOAc:heptane (1:1)]to give the title compound (232 mg, 67%) as a pale yellow solid.

Method O

6-(5-Chloro-2-thienyl)-1H-purine-2-amine (Example 129)

A solution of N,9-bis(tetrahydropyran-2-yl)-6-chloro-9H-purine-2-amine (1.01 g, 3.0 mmol) and Pd(PPh₃)₄ (250 mg, 10 mol %) in THF (20 mL) was treated with 5-chloro-2-thiopheneboronic acid (536 mg, 3.3 mmol) and saturated aq NaHCO₃ (10 mL), refluxed for 1 h, diluted with H₂O, extracted with EtOAc and the organic phase dried (MgSO₄), concentrated in vacuo and purified by chromatography [SiO₂; heptane:EtOAc (2:1)] to give the coupled product as a pale-yellow syrup. This material was dissolved in MeOH (20 mL) and stirred vigorously at 50° C. with Amberlyst-15 resin for 1 hr. The resin was filtered off, washed once with MeOH, and then re-suspended in fresh MeOH (20 mL), treated with NH₃ solution (2-M in MeOH, 2.0 mL), stirred vigorously at 50° C. for 1 h, filtered, the resin washed twice with MeOH, and the filtrate concentrated in vacuo to give the title compound (230 mg, 36%) as a yellow solid.

Method P

2-Amino-6-(2-furyl)-N-phenyl-9H-purine-9-acetamide (Example 85)

A solution of 2-amino-6-(2-furyl)-9H-purine-9-acetic acid (129 mg, 0.5 mmol) in DCM (2 mL) was treated with EDCI (96 mg, 0.5 mmol) and aniline (45 μL, 0.5 mmol), stirred at room temperature for 3 days, diluted with DCM, washed with water, dried (MgSO₄), concentrated in vacuo and purified by chromatography (SiO₂; 1% MeOH in EtOAc) to give the title compound (51 mg, 31%) as a white solid.

Method Q

2-Amino-N-benzyl-6-(2-furyl)-9H-purine-9-acetamide (Example 86)

A suspension of 2-amino-6-(2-furyl)-9H-purine-9-acetic acid (129 mg, 0.5 mmol) in DMF (2 μL) was treated with carbonyl diimidazole (81 mg, 0.5 mmol), stirred at room temperature for 1 h, treated with benzylamine (55 μL, 0.5 mmol), stirred at room temperature for 2 h, diluted with water, filtered and dried to give the title compound (115 mg, 66%) as a white solid.

Method R

6-(5-Methyl-[1,2,4]-oxadiazol-3-yl)-1H-purine-2-amine (Example 90)

A mixture of hydroxylamine hydrochloride (847 mg, 12.2 mmol) and potassium hydroxide (855 mg, 15.3 mmol) in EtOH was refluxed for 30 min, cooled, filtered to remove solid potassium chloride, treated with 9-(2-tetrahydropyranyl)-2-(2-tetrahydropyranylamino)-9H-purine-6-carbonitrile (1.0 g, 3.05 mmol), refluxed for 1 h, concentrated in vacuo and the residue triturated with Et₂O to give a pale yellow solid (1.12 g). A portion (600 mg) of this material was stirred with N,N-dimethylacetamide dimethylacetal at 100° C. for 1 h, concentrated in vacuo and purified by chromatography (SiO₂; EtOAc) to give a pale yellow syrup (212 mg). This material was dissolved in MeOH and stirred vigorously at 50° C. with Amberlyst-15 resin for 1 hr and the resin filtered off and washed once with MeOH. The resin was then re-suspended in fresh MeOH, treated with a solution of NH₃ in MeOH (2-M, 2 mL), stirred vigorously at 60° C. for 1 h, filtered, washed twice with MeOH, and the filtrate concentrated in vacuo to give the title compound (73 mg, 21%) as a pale grey solid.

Method S

6-(2-Furyl)-9-(2-(2-pyridyl)ethyl)-9H-purine-2-amine (Example 102)

A mixture of 6-(2-furyl)-1H-purine-2-amine (50 mg, 0.25 mmol) and triphenylphosphine polystyrene (0.21 g, 0.62 mmol) in anhydrous DMF (0.5 mL) and anhydrous THE (2 mL) was treated with 2-(2-hydroxyethyl)pyridine (61 mg, 0.50 mmol), shaken at room temperature for 10 min, treated with di-tert-butyl azodicarboxylate (0.115 g, 0.50 mmol), shaken for 16 h, filtered and the filtrate concentrated in vacuo and purified by chromatography [SiO₂; CH₂Cl₂-MeOH (100:5)] to give the title compound (36 mg, 47%) as an off-white solid.

Method T

Benzyl 2-amino-6-(2-furyl)-9H-purine-9-carboxylate (Example 106)

A solution of 6-(2-furyl)-1H-purine-2-amine (0.201 g, 1.0 mmol), benzyl chloroformate (0.20 mL, 1.1 mmol), triethylamine (0.21 mL, 1.5 mmol) and DMAP (15 mg) in DMF (10 mL) was stirred at room temperature for 4 h, poured into cold water, cooled for 30 min at 5° C. and the resulting solid filtered and dried at 40° C. to give the title compound (0.327 g, 98%) as a cream solid.

Method X Ethyl 2,6-dichloro-9H-purine-9-acetate

An ice-cold solution of 2,6-dichloro-1H-purine (1.89 g, 10 mmol) in THF (10 mL) was treated with NaH (60% in oil, 440 mg, 11 mmol), stirred at 0° C. for 30 min, treated with ethyl bromoacetate (1.22 mL, 11 mmol), stirred at room temperature for 2 h, poured into sat. NaHCO₃, extracted with EtOAc and the combined organic phase dried (MgSO₄), concentrated in vacuo and purified by chromatography [SiO₂; Heptane:EtOAc (2:1)] to give the title compound (1.46 g, 53%) as a white solid: IR ν_(max) (Nujol)/cm⁻¹ 3106, 2985, 2955, 2924, 2854, 1734, 1598, 1557, 1374, 1341, 1298, 1156 and 884; NMR δ_(H) (400 MHz, CDCl₃) 1.31 (3H, t, J 7.0 Hz), 4.29 (2H, q, J 7.0 Hz), 5.01 (2H, s), 8.17 (1H, s).

Method Y

6-(5-Methyl-2-furyl)-1H-purine-2-amine (Example 195)

A solution of N,9-bis(tetrahydropyran-2-yl)-4-chloro-9H-purine-2-amine (338 mg, 1 mmol), 5-methyl-2-(tributylstannyl)furan and Pd(PPh₃)₂C₂ (70 mg) in DMF was heated at 80° C. for 5 h, cooled, diluted with H₂O, extracted with EtOAc and the organic phase dried (MgSO₄), concentrated in vacuo and purified by chromatography [SiO₂; heptane:EtOAc (6:1)] to give the coupled product. This material was dissolved in MeOH (20 mL), stirred vigorously at 50° C. with Amberlyst-15 resin for 1 h then the resin was filtered off and washed once with MeOH. The resin was then re-suspended in fresh MeOH (20 mL), treated with NH₃ solution (2-M in MeOH, 1.0 mL) stirred vigorously at 50° C. for 1 h, filtered, washed twice with MeOH, and the filtrate concentrated in vacuo to give the title compound (45 mg, 21%) as a pale-yellow solid.

Method Z

6-(5-Methyl-2-pyridinyl)-1H-purine-2-amine (Example 241)

A stirred solution of 5-methyl-2-pyridylzinc bromide (0.5 M, 8 mL, 4 mmol) was treated with Pd(PPh₃)₄ (250 mg) and N,9-bis(tetrahydropyran-2-yl)-4-chloro-9H-purine-2-amine (676 mg, 2 mmol), refluxed for 1 h, cooled, diluted with H₂O, extracted with EtOAc, the extracts dried (MgSO₄), concentrated in vacuo and purified by chromatography [SiO₂; heptane:EtOAc (1:2), then EtOAc] to give the coupled product (498 mg). A portion of this material (100 mg) was suspended in MeOH, treated with a solution of HCl (4-M in dioxan, 0.5 mL), stirred for 17 h, diluted with Et₂O and filtered to afford the title compound (37 mg, 35%) as a yellow solid.

Method AA

Methyl 3-(2-amino-6-(2-furyl)-9H-purine-9-yl)propionate (Example 151)

A solution of 6-(2-furyl)-1H-purine-2-amine (0.70 g, 3.48 mmol) and K₂CO₃ (0.48 g, 3.48 mmol) in DMF (20 mL) was treated with methyl acrylate (3.3 g, 38.3 mmol), stirred for 40 h, diluted with EtOAc, filtered to remove polymeric acrylate, washed with water, dried (MgSO₄), concentrated in vacuo and purified by chromatography [SiO₂:EtOAc-heptane, (4:1)] to give the title compound (114 mg, 11%) as a white solid.

Method AB

6-(2-Furyl)-2-methyl-1H-purine (Example 153)

A solution of 2-chloro-6-(2-furyl)-1H-purine (1.1 g, 5.0 mmol) and Pd(PPh₃)₄ (0.58 g, 0.5 mmol) in 1,2-dichloroethane (50 mL) at room temperature was treated dropwise with trimethylaluminium (3.3 mL, 2.0 M hexane), refluxed for 16 h, treated with water (100 mL) then EtOAc (100 mL), stirred for 60 h and filtered through glass microfibre paper. The organic phase was separated, dried (MgSO₄), concentrated in vacuo and the resulting solid recrystallised from 90% ethanol to give the title compound (0.30 g, 30%) as a pale brown solid.

Method AC

6-(2-Furyl)-9-(3-nitrobenzyl)-9H-purine-2-amine (Example 158)

An ice-cold solution of 6-(2-furyl)-1H-purine-2-amine (201 mg, 1 mmol) in DMF (6 mL) was treated with NaH (44 mg, 1.1 mmol), stirred for 30 min, treated with 3-nitrobenzyl bromide (238 mg, 1.1 mmol), stirred at room temperature for 3 h, treated with water and the resulting solid filtered, suspended in methanol, stirred for 30 min, and filtered to give the title compound (201 mg, 60%) as a yellow solid.

Method AD

9-(3-Aminobenzyl)-6-(2-furyl)-9H-purine-2-amine (Example 192)

A solution of 6-(2-furyl)-9-(3-nitrobenzyl)-9H-purine-2-amine (400 mg, 1.12 mmol) in EtOH (10 mL) at 50° C. was treated with a solution of SnCl₂.2H₂O (808 mg, 3.58 mmol) in conc.HCl (1.8 ml, 21.42 mmol), stirred for 1.5 h, cooled, basified to pH 10 (1-M NaOH) and the resulting solid was filtered, suspended in methanol, treated with HCl in dioxane (4-M, 2 mL), diluted with diethyl ether and filtered to give the title compound (90 mg, 22%) as a yellow solid.

Method AF

9-(3-Acetamidobenzyl)-6-(2-furyl)-9H-purine-2-amine (Example 205)

An ice-cold solution of 9-(3-aminobenzyl)-6-(2-furyl)-9H-purine-2-amine (145 mg, 0.48 mmol) in pyridine (3 mL) was treated with acetyl chloride (38 μL, 0.53 mmol), stirred for 1 h, quenched with water, extracted with EtOAc, dried (MgSO₄), concentrated in vacuo and purified by chromatography (SiO₂:Hexane:EtOAc (1:3) to EtOAc:MeOH (99:1)) to give the title compound (71 mg, 43%) as a yellow solid.

Method AG

6-(2-Furyl)-9-(3-hydroxybenzyl)-9H-purine-2-amine (Example 221)

An ice-cold solution of 6-(2-furyl)-9-(3-methoxybenzyl)-9H-purine-2-amine (160 mg, 0.5 mmol) in DCM (3 mL) was treated with BBr₃ (1 mL, 1-M in DCM 1 mmol), stirred at 0° C. for 3 h, treated with more BBr₃ (2 mL, 1-M in DCM, 2 mmol), stirred for 16 h, treated with NH₄Cl solution, extracted with EtOAc, dried (MgSO₄), concentrated in vacuo, triturated with ether and filtered. The resulting solid was suspended in aqueous sodium bicarbonate, extracted with ether, the aqueous phase was acidified to pH 7 and the resulting solid filtered, suspended in methanol, treated with HCl in dioxane (4-M, 2 mL), diluted with ether and filtered to give the title compound (82 mg, 48%) as a yellow solid.

Method AH

6-(2-Furyl)-9-(4-methylbenzyl)-9H-purine-2-carbonitrile (Example 173)

A solution of 2-chloro-6-(2-furyl)-9-(4-methylbenzyl)-9H-purine (0.10 g, 0.31 mmol) and Et₄NCN (0.10 g, 0.62 mmol) in acetonitrile (10 mL) was treated with DABCO (0.07 g, 0.62 mmol), stirred for 48 h, concentrated in vacuo, dissolved in chloroform (50 mL), washed with water (2×30 mL), dried (MgSO₄) and concentrated in vacuo to give the title compound (56 mg, 57%) as a pale green solid.

Method AI

2-Amino-9-(2-fluorobenzyl)-9H-purine-6-thiocarboxamide

A suspension of 2-amino-9-(2-fluorobenzyl)-9H-purine-6-carbonitrile (680 mg, 1.85 mmol) in isopropanol (50 mL) was treated with H₂S gas for 15 min, then treated with Et₃N (0.51 mL, 3.7 mmol), heated at 50° C. for 1 h, concentrated in vacuo, diluted with Et₂O and filtered to give the title compound (757 mg, 100%) as a yellow solid; NMR δ_(H) (400 MHz, DMSO) 5.36 (2H, s), 6.66 (2H, br s), 7.06-7.43 (4H, m), 8.15 (1H, s), 9.81 (1H, br s) and 10.22 (1H, br s).

Method AJ

9-(2-Fluorobenzyl)-6-(4-methyl-2-thiazolyl)-9H-purine-2-amine (Example 244)

A stirred suspension of 2-amino-9-(2-fluorobenzyl)-9H-purine-6-thiocarboxamide (200 mg, 0.5 mmol) and chloroacetone (1 mL) in isopropanol (5 mL) was heated at 80° C. for 2 h, filtered and the filtrate concentrated in vacuo and purified by chromatography [SiO₂; EtOAc] to give the title compound (26 mg, 12%) as a yellow solid.

Method AK

2-Amino-N-benzyl-6-(2-furyl)-9H-purine-9-acetimidamide (Example 245)

A solution of 2-amino-6-(2-furyl)-9H-purine-9-acetonitrile (0.24 g, 1.0 mmol) in dry toluene (5 mL) under argon was treated with N-benzylmethylchloroaluminium amide in toluene (1.2-M, 5 mL, 6.0 mmol), heated to 80° C. for 3 h, stirred at room temperature for 16 h, poured into a slurry of SiO₂ (5 g) and CHCl₃ (25 mL) and stirred for 5 min. The slurry was filtered, the filtrate concentrated in vacuo and the resulting solid purified by chromatography [SiO₂; CH₂Cl₂-MeOH—NHOH (100:10:1)] to give the title compound (0.16 g, 46%) as a white solid.

Method AL

(2S)-9-(2-Amino-1-propyl)-6-(2-furyl)-9H-purine-2-amine (Example 251)

A solution of the 6-(2-furyl)-1H-purine-2-amine (0.1 g, 0.5 mmol) in DMSO was treated with fleshly ground KOH (112 mg, 2 mmol), shaken for 10 min, treated with N-butoxycarbonyl-L-alaninol mesylate (316 mg, 3 mmol), shaken at 40° C. for a further 17 h, treated with di-tert-butyl dicarbonate (655 mg, 3 mmol), shaken for a further 30 min, diluted with H₂O, extracted with EtOAc and the extracts dried (MgSO₄), concentrated in vacuo and purified by chromatography [SiO₂; (EtOAc)]. The resulting gelatinous solid was dissolved in MeOH (3 mL), treated with HCl solution (4-M in dioxan, 0.5 mL), stirred for 17 h, diluted with Et₂O and filtered to give the title compound (67 mg, 45%) as a yellow solid.

Method AM

9-(2-fluorobenzyl)-6-(1H-pyrazol-3-yl)-9H-purine-2-amine (Example 262)

A mixture of 1-(2-trimethylsilylethoxymethyl)-1H-pyrazole-5-boronic acid, Pd(PPh₃)₄ and saturated aqueous NaHCO₃ in THF was refluxed with vigorous stirring for 1 h, cooled, diluted with EtOAc, washed with water, dried (MgSO₄), concentrated in vacuo and purified by chromatography [SiO₂; isohexane:EtOAc (2:1)] to give the coupled product. This material was dissolved in MeOH (2 mL), treated with HCl solution (4-M in dioxan, 2 mL), stirred for 17 h, diluted with Et₂O and filtered to give the title compound (161 mg, 46%) as a cream solid.

Method AO

9-(3-Aminobenzyl)-6-(5-methyl-1H-pyrazol-3-yl)-1H-purine-2-amine (Example 265)

A mixture of 6-chloro-9-(3-nitrobenzyl)-1H-purine-2-amine (304 mg, 1 mmol), 1-((2-trimethylsilylethoxy)methyl)-1H-pyrazole-5-boronic acid (2.4 mmol), Pd(PPh₃)₄ (110 mg, 10 mol %) and saturated NaHCO₃ (5 mL) in THF (20 mL) was refluxed for 3 h, treated with more Pd(PPh₃)₄ (50 mg, 5 mol %) and refluxed for a further 17 h. The mixture was diluted with H₂O (50 mL), extracted with EtOAc (2×25 mL), dried (MgSO₄), concentrated in vacuo and purified by chromatography [SiO₂; iso-hexane:EtOAc (1:2)] to afford a brown gum. This material was treated with MeOH (10 mL) and 10% Pd/C, stirred under an atmosphere of hydrogen for 30 min, filtered through a pad of Celite and concentrated in vacuo. The resulting gum was dissolved in MeOH (5 mL), treated with HCl solution (4-M in dioxane, 1 mL), stirred for 17 h and the filtered to give the title compound (25 mg, 7%) as a grey solid.

Method AP

2-Allyloxymethyl-6-bromomethylpyridine

A solution of 6-allyloxymethylpyridine-2-methanol (1.56 g, 8.72 mmol) and triphenylphosphine (2.74 g, 10.5 mmol) in dichloromethane (40 mL) at 0° C. was treated portionwise with CBr₄ (4.34 g, 13.1 mmol), stirred for 1 h, concentrated in vacuo and purified by chromatography [SiO₂; isohexane:EtOAc (3:1)] to give the title compound (1.99 g, 94%) as a colourless oil: NMR H (400 MHz, CDCl₃) 7.71 (1H, t, J 7.5 Hz), 7.40 (1H, d, J 7.5 Hz), 7.34 (1H, d, J 7.5 Hz), 6.03-5.93 (1H, m), 5.37-5.32 (1H, m), 5.26-5.22 (1H, m), 4.64 (2H, s), 4.54 (2H, s) and 4.14-4.12 (2H, m).

Method AQ

6-(2-Furyl)-9-(5-indolylmethyl)-1H-purine-2-amine (Example 272)

A solution of tert-butyl 5-(2-amino-6-(2-furyl)-1N-purine-9-ylmethyl)indole-1-carboxylate (352 mg, 0.82 mmol) in MeOH (3 mL) was treated with NaOMe (221 mg, 4.1 mmol), refluxed for 17 h, diluted with water (10 mL) and filtered to give the title compound (168 mg, 62%) as a brown powder.

Method AR

tert-Butyl 5-bromomethylindole-1-carboxylate

A solution of tert-butyl 5-methylindole-1-carboxylate (2.07 g, 9.0 mmol) in CCl₄ (50 mL) was treated with N-bromosuccinimide (1.60 g, 9.0 mmol) and benzoyl peroxide (75% in H₂O, 276 mg, 9.0 mmol), refluxed for 3 h, concentrated in vacuo and purified by chromatography [SiO₂; iso-hexane:EtOAc (20:1)] to give the title compound (1.67 g, 60%) as an orange oil: NMR δ_(H) (400 MHz, CDCl₃) 8.11 (1H, br d, J 8.5 Hz), 6.72 (1H, d, J 3.5 Hz), 7.59 (1H, d, J 1.5 Hz), 7.35 (1H, dd, J 8.5, 1.5 Hz), 6.54 (1H, d, J 4.0 Hz), 4.64 (2H, s) and 1.67 (9H, s).

Method AS

6-Allyloxymethyl-2-pyridinemethanol

A solution of 2,6-pyridinedimethanol (5.0 g, 35.9 mmol) in DMF (30 mL) at 0° C. was treated with sodium hydride (1.44 g, 35.9 mmol), stirred for 30 min, treated with allyl bromide (3.42 ml, 39.5 mmol), stirred for 16 h at room temperature, poured into water (150 mL), extracted with EtOAc (3×30 mL) and the combined organic phase was dried (MgSO₄), concentrated in vacuo and purified by chromatography [SiO₂; isohexane:EtOAc (3:1 to 1:1)] to give the title compound (1.56 g, 24%) as a colourless oil: NMR δ_(H) (400 MHz, CDCl₃) 7.69 (1H, t, J 7.5 Hz), 7.37 (1H, d, J 7.5 Hz), 7.13 (1H, d, J 7.5 Hz), 6.04-5.93 (1H, m), 5.38-5.21 (2H, m), 4.74 (2H, d, J 5.0 Hz), 4.65 (2H, s), 4.15-4.09 (2H, m) and 3.76 (1H, t, J 5.0 Hz).

The following intermediates were synthesised by the methods described above.

6-Chloro-9-(3-nitrobenzyl)-1H-purine-2-anine

This was prepared from 6-chloro-1H-purine-2-amine by method AC: NMR δ_(H) (400 MHz, DMSO) 8.82 (1H, s), 8.20-8.13 (2H, m), 7.73-7.61 (2H, m), 6.94 (2H, br s) and 5.45 (2H, s).

6-Chloro-9-(3-methoxybenzyl)-1H-purine-2-amine

This was prepared from 6-chloro-1H-purine-2-amine by method AC: NMR δ_(H) (400 MHz, DMSO) 8.22 (1H, s), 7.25 (1H, t, J 7.5 Hz), 6.91 (2H, br s), 6.89-6.84 (2H, m), 6.79 (1H, d, J 7.5 Hz), 5.25 (2×, s) and 3.72 (3H, s).

6-Chloro-9-(2-fluorobenzyl)-1H-purine-2-amine

This was prepared from 6-chloro-1H-purine-2-amine by method AC: IR (Nujol)/cm⁻¹ 3488, 3379, 2926, 1569, 1568, 1465, 1378, 918 and 756; NMR δ_(H) (400 MHz, DMSO) 8.17 (1H, s), 7.43-7.33 (1H, m), 7.29-7.21 (1H, m), 7.20-7.07 (2H, m), 6.91 (2H, br s) and 5.35 (2H, s).

2,6-Dichloro-9-(2-trimethylsilylethoxymethyl)-9H-purine

This was prepared from 2,6-dichloro-1H-purine by method X to give the title compound (1.77 g, 78%) as a pale yellow oil; NMR H (400 M, CDCl₃) 0.00 (9H, s), 0.94 (2H, t, J 8.3 Hz), 3.63 (2H, t, J 8.3 Hz), 5.63 (2H, s) and 8.25 (1H, s).

tert-Butyl 2-amino-6-chloro-9H-purine-9-carboxylate

This was prepared from 6-chloro-1H-purine-2-amine and di-tert-butyl dicarbonate by method G to give title compound (862 mg, 64%) as a white solid; mp>350° C.; IR ν_(max) (Nujol)/cm⁻¹ 3521, 3304, 3193, 3129, 2955, 2925, 2854, 1772, 1730, 1632, 1561, 1511, 1367, 1308 and 1155; NMR δ_(H) (400 MHz, DMSO) 1.58 (9H, s), 7.06 (2H, s), 8.36 (1H, s). Anal. Calcd for C₁₀H₁₂ClN₅O₂: C, 44.54; H, 4.48; N, 25.96. Found: C, 44.27; H, 4.54; N, 25.88.

Isobutyl 2-amino-6-chloro-9H-purine-9-carboxylate

This was prepared from 6-chloro-1H-purine-2-amine by method T to give the title compound (528 mg, 98%) as a white solid; IR ν_(max) (Nujol)/cm⁻¹ 3519, 3310, 3201, 3124, 2955, 2925, 2854, 1778, 1624, 1560, 1469, 1367, 1301 and 1186; NMR δ_(H) (400 MHz, CDCl₃) 1.07 (6H, d, J 7.0 Hz), 2.10-2.25 (1H, m), 4.29 (2H, d, J 6.6 Hz), 5.48 (2H, s) and 8.25 (1H, s).

2-Amino-N-tert-butyl-6-chloro-9H-purine-9-carboxamide

This was prepared from 6-chloro-1H-purine-2-amine by method G to give the title compound (286 mg, 53%) as a white solid; IR ν_(max) (Nujol)/cm⁻¹ 3501, 3299, 3190, 3156, 2993, 2955, 2924, 2854, 1742, 1627, 1563, 1506 and 1369; NMR δ_(H) (400 MHz, CDCl₃) 1.46 (9H, s), 7.40 (1H, s), 8.45 (1H, s) and 8.57 (1H, s).

Phenyl 2-amino-6-chloro-9H-purine-9-carboxylate

This was prepared from 6-chloro-1H-purine-2-amine by method T to give the crude title compound (625 mg, 100%) as a white solid.

2-Amino-6-chloro-N-phenyl-9H-purine-9-carboxamide

This was prepared from 6-chloro-1H-purine-2-amine by method G to give the title compound (424 mg, 73%) as a white solid; IR ν_(max) (Nujol)/cm⁻¹ 3506, 3333, 3292, 3191, 3140, 2925, 2854, 1740, 1653, 1637, 1562, 1481 and 1367; NMR δ_(H) (400 MHz, DMSO) 7.20 (1H, m), 7.44-7.50 (2H, m), 7.61 (2H, s), 7.75-7.81 (2H, m), 8.60 (1H, s), 10.86 (1H, s).

2-Amino-6-chloro-N-ethyl-9H-purine-9-carboxamide

This was prepared from 6-chloro-1H-purine-2-amine by method G to give the title compound (449 mg, 93%) as a white solid; IR ν_(max) (Nujol)/cm⁻¹ 3404, 3324, 3304, 3222, 3125, 2925, 2854, 1730, 1646, 1614, 1547, 1514, 1484, 1460, 1370 and 1228; NMR δ_(H) (400 MHz, DMSO) 1.25 (3H, t, J 7.0 Hz), 3.37-3.46 (2×, m), 7.37 (2H, s), 8.47 (1×, s), 8.64 (1H, t, J 5.5 Hz).

2-Amino-6-chloro-N-cyclohexyl-9H-purine-9-carboxamide

This was prepared from 6-chloro-1H-purine-2-amine by method G to give the title compound (1.66 g, 53%) as a white solid; NMR δ_(H) (400 MHz, CDCl₃) 1.29-1.41 (1H, m), 1.42-1.54 (4H, m), 1.60-1.70 (1H, m), 1.74-1.86 (2H, m), 2.00-2.10 (2H, m), 3.88-4.00 (1H, m), 8.13 (1H, d, J 6.7 Hz) and 8.81 (1H, s).

2-Amino-9-(2-fluorobenzyl)-9H-purine-6-carbonitrile

This was prepared from 6-chloro-9-(2-fluorobenzyl)-9H-purine-2-amine by method AH to give the title compound (450 mg, 84%) as a cream solid; NMR δ_(H) (400 MHz, DMSO) 5.39 (2H, s), 7.12 (2H, br s), 7.1207.45 (4H, m) and 8.41 (1H, s).

Table 2—Analytical Data

HPLC is carried out using the following conditions: Column. Waters Xterra RP 18 (50×4.6 mm); Particle size 5 μM; Mobile phase MeOH:10 mM aq NH₄OAc (pH 7 buffer); Gradient 50:50 isocratic for 1 min. then linear gradient 50:50 to 80:20 over 5 min. then 80:20 isocratic for 3 mL/min.; Flow rate 2.0 mL/min.; Detection wavelength λ=230 nM. Retention times are provided in Table 2.

Alternatively HPLC is carried out using the following conditions: Column. Supelcosil ABZ⁺ (170×4.6 mm), particle size 5 μM, mobile phase MeOH: 10 mM aq NH₄OAc (80:20), (80:50), (70:30), (60:40) or (50:20) (specified in Table 2), flow rate 1.0 mL/min., detection wavelength λ=230 nM. Retention times and mobile phase ratio are provided in TABLE 2 Example Method Yield(%) Data 1 A 70 mp 105.8-106.2° C.; IR ν_(max)(Nujol)/cm⁻¹ 3552, 3146, 3892, 3082, 2954, 2924, 2854, 1589, 1566, 1484, 1370, 1319, 1250, 1219 1162, 1095 and 841; NMR δ_(H)(400MHz, CDCl₃) 0.0(9H, s), 0.97(2H, t, J 8.3Hz), 3.66(2H, t, J 8.3Hz), 5.66(2H, s), 6.69-6.73(1H, m), 7.82(1H, s), 7.92(1H, d, J 3.5Hz) and 8.24(1H, s); Anal. Calcd for C₁₅H₁₉ClN₄O₂Si: C, 51.35; H, 5.46; N, 15.96. Found: C, 51.39; H, 5.45; N, 15.97. 2 B 86 mp 81.5-82.2° C.; IR ν_(max)(Nujol)/cm⁻¹ 3142, 3109, 2927, 2854, 1601, 1585, 1560, 1465, 1397, 1372 and 1106; NMR δ_(H)(400MHz, DMSO) −0.04(9H, s), 0.95(2H, t, J 8.3Hz), 3.29(6H, s), 3.64(2H, t, J 8.3Hz), 5.51(2H, s), 6.60-6.63(1H, m), 7.67(1H, d, J 2.5Hz); 7.73-7.74(1H, m) and 7.87(1H, s); Anal. Calcd for C₁₇H₂₅N₅O₂Si: C, 56.80; H, 7.01; N, 19.47. Found: C, 56.40; H, 6.98; N, 19.27. 3 C 76 IR ν_(max)(Nujol)/cm⁻¹ 3132, 3105, 2924, 2854, 1631, 1588, 1563, 1538, 1466, 1401, 1364, 832 and 780; NMR δ_(H)(400MHz, DMSO) 3.21(6H, s), 6.74-6.80(1H, m), 7.77(1H, d, J 2.9Hz), 8.00(1H, s), 8.11(1H, s), 12.76(1H, s); Anal. Calcd for C₁₁H₁₁N₅O.0.1 H₂O: C, 57.18; H, 4.89; N, 30.31. Found: C, 57.14; H, 4.81; N, 30.26. 4 B 60 mp 125.9-126.4° C.; IR ν_(max)(Nujol)/cm⁻¹ 3376, 3327, 2955, 2924, 2854, 1605, 1588, 1537, 1462, 1410, 1367, 1356, 1248, 1094 and 835; NMR δ_(H)(400MHz, CDCl₃) −0.03(9H, s), 0.94(2H, t, J 8.3Hz), 1.21(1H, d, J 6.5Hz), 3.61(2H, t, J 8.3Hz), 3.69(2H, q, 5.6Hz), 3.90(2H, q, J 4.8Hz), 5.49(2H, s), 5.56-5.64(1H, m), 6.62-6.66(1H, m), 7.72(1H, d, J 5.6Hz) and 7.79(1H, d, J 3.5Hz). 5 C 86 mp 227.1-228.1° C.; IR ν_(max)(Nujol)/cm⁻¹ 3428, 3113, 2924, 2854, 1626, 1588, 1576, 1541, 1485, 1457, 1404 and 1371; NMR δ_(H)(400MHz, DMSO) 3.41(2H, q, J 6.0Hz), 3.53-3.62(2H, m), 4.67-4.76(1H, s), 6.74-6.79(1H, m), 6.81-6.94(1H, s), 7.69-7.78(1H, s), 7.98(1H, s), 8.05-8.15(1H, s) and 12.68-12.81(1H, s). 7 A 48 mp >305° C. dec.; IR ν_(max)(Nujol)/cm⁻¹ 3130, 3111, 2925, 2854, 1776, 1755, 1596, 1558, 1467, 1373, 1302, 1288, 1153 and 1135; NMR δ_(H)(400MHz, CDCl₃) 1.71(9H, s), 6.63-6.72(1H, m), 7.78-7.81(1H, m), 7.90(1H, d J 3.5Hz) and 8.50(1H, s); Anal. Calcd for C₁₄H₁₃ClN₄O₃: C, 52.43; H, 4.09; N, 17.46. Found: C, 52.68; H, 4.08; N, 17.50. 8 A 61 mp >303° C. dec.; IR ν_(max)(Nujol)/cm⁻¹ 3101, 3042, 2927, 2854, 1628, 1556, 1448, 1364, 1283, 1166, 1023, 921, 837 and 752; NMR δ_(H)(400MHz, DMSO) 6.84-6.91(1H, m), 7.73-7.93(1H, s), 8.13(1H, s), 8.65-8.75(1H, s) and 13.71-13.84(1H, s); Anal. Calcd for C₉H₅ClN₄O: C, 49.00; H, 2.28; N, 25.38. Found: C, 48.78; H, 2.54; N, 25.10. 9 B 64 mp 130.9-131.5° C.; IR ν_(max)(Nujol)/cm⁻¹ 3526, 3218, 3111, 3070, 2924, 2855, 2733, 1629, 1600, 1560, 1518, 1463, 1375 and 835; NMR δ_(H)(400MHz, DMSO) 1.85-2.08(4H, m), 3.42-3.66(3H, m), 3.67-3.78(1H, m), 4.15-4.25(1H, s), 4.81-5.09(1H, s), 6.76-6.80(1H, m), 7.73-7.79(1H, s), 8.01(1H, s), 8.09-8.16(1H, s) and 12.78-12.87(1H, s); Anal. Calcd for C₁₄H₁₅N₅O₂: C, 56.27; H, 5.57; N, 23.44. Found: C, 56.35; H, 5.52; N, 23.18. 10 B 50 mp >206.5-207.4° C.; IR ν_(max)(Nujol)/cm⁻¹ 3389, 3121, 2924, 2854, 1620, 1590, 1570 1539, 1515, 1465 and 1026; NMR δ_(H)(400MHz, DMSO) 3.71(3H, s), 3.73(3H, s), 4.49(2H, d, J 5.9Hz), 6.77(1H, s), 6.82-6.94(2H, m), 7.06(1H, s), 7.41-7.56(1H, s), 7.76(1H, s), 7.98(1H, s), 8.08(1H, s) and 12.72(1H, s); Anal. Calcd for C₁₄H₁₅N₅O₂.0.5 H₂O: C, 59.99; H, 5.03; N, 19.43. Found: C, 59.81; H, 4.75; N, 19.07. 11 D 57 mp >230° C. dec.; IR ν_(max)(Nujol)/cm⁻¹ 3370, 3134, 3085, 2924, 2854, 2481, 1674, 1616 and 1465; NMR δ_(H)(400MHz, DMSO) 6.91-6.97(1H, m), 7.91(1H, s), 8.25(1H, s) and 8.71(1H, s); M/Z 202(M+H)⁺. 12 E 32 mp 112.0-113.0° C.; IR ν_(max)(Nujol)/cm⁻¹ 3113, 2925, 2854, 1775, 1749, 1596, 1460, 1374, 1303, 1139 and 762; NMR δ_(H)(400MHz, CDCl₃) 1.72(9H, s), 2.68(3H, s), 6.63-6.68(1H, m), 7.77(1H, s), 7.82(1H, d, J 3.6Hz) and 8.44(1H, s). 13 F 86 mp 239.5-239.9° C.; IR ν_(max)(Nujol)/cm⁻¹ 3371, 3044, 2924, 2854, 2703, 1624, 1606, 1584, 1563, 1465, 1307 and 843; NMR δ_(H)(400MHz, DMSO) 2.61(3H, s), 3.93-5.45(2H, s), 6.80-6.86(1H, m), 7.79(1H, d, J 3.6Hz), 8.07-8.09(1H, m) and 8.53(1H, s); Anal. Calcd for C₁₀H₈N₄O₅.0.25 HCl.0.5 H₂O: C, 48.26; H, 3.71; N, 22.14. Found: C, 47.97; H, 3.72; N, 22.38. 14 A 69 mp 143.2-144.1° C.; IR ν_(max)(Nujol)/cm⁻¹ 3512, 3394, 3324, 3215, 2955, 2925, 2854, 1769, 1749, 1639, 1587, 1565, 1372, 1298 and 1143; NMR δ_(H)(400MHz, CDCl₃) 1.68(9H, s), 5.38(2H, s), 6.62-6.66(1H, m), 7.71-7.73(1H, m), 7.82(1H, d, J 3.6Hz) and 8.17(1H, s); Anal. Calcd for C₁₄H₁₅N₅O₃: C, 55.81; H, 5.02; N, 23.23. Found: C, 55.73; H, 5.06; N, 22.84. 15 B 45 mp 185.5-186° C.; IR ν_(max)(Nujol)/cm⁻¹ 3307, 3141, 3077, 2954, 2924, 2854, 1604, 1542, 1460, 1368, 1247 and 1093; NMR δ_(H)(400MHz, CDCl₃) 0.00(9H, s), 0.97(2H, t, J 8.3Hz), 3.66(2H, t, J 8.3Hz), 4.19(2H, t, J 5.8Hz), 5.15-5.20(1H, m), 5.30-5.37(1H, m), 5.54(2H, s), 5.96-6.09(1H, m), 6.63-6.69(1H, m), 7.74-7.76(1H, m), 7.81(1H, d, J 3.5Hz) and 7.92(1H, s); Anal. Calcd for C₁₈H₂₅N₅O₂Si: C, 58.19; H, 6.78; N, 18.84. Found: C, 58.14; H, 6.80; N, 18.73. 16 B 82 mp 160.1-160.8° C.; IR ν_(max)(Nujol)/cm⁻¹ 3312, 3143, 3095, 2924, 2854, 1605, 1580, 1552, 1467, 1396, 1367, 1249 and 1092; NMR δ_(H)(400MHz, CDCl₃) 0.00(9H, s), 0.99(2H, t, J 8.3Hz), 3.11(3H, d, J 5.0Hz), 3.68(2H, t, J 8.3Hz), 5.21-5.29(1H, s), 5.56(2H, s), 6.64-6.69(1H, m), 7.74(1H, s), 7.81(1H, d, 2.9Hz) and 7.91(1H, s); Anal. Calcd for C₁₆H₂₃N₅O₂Si.0.2 H₂O: C, 55.05; H, 6.76; N, 20.06. Found: C, 55.03; H, 6.60; N, 20.12. 17 C 58 mp 158.7-160.1° C.; IR ν_(max)(Nujol)/cm⁻¹ 3397, 3528, 3084, 2924, 2854, 1626, 1592, 1536 and 1460; NMR δ_(H)(400MHz, DMSO) 3.99(2H, t, J 4.9Hz), 5.06(1H, d, J 10.2Hz), 5.21(1H, d, J 18.9Hz), 5.91-6.03(1H, m), 6.72-6.79(1H, m), 7.12-7.20(1H, s), 7.76(1H, d, J 3.0Hz), 7.97(1H, s) and 8.08(1H, s). 18 C 81 mp 235-236° C. dec.; IR ν_(max)(Nujol)/cm⁻¹ 3311, 3102, 2924, 2854, 1630, 1587, 1555, 1460, 1400 and 1370; NMR δ_(H)(400MHz, DMSO) 2.87(3H, d, J 4.8Hz), 6.74-6.78(1H, m), 6.90-7.01(1H, s), 7.76(1H, d, J 3.5Hz), 7.96(1H, s) and 8.07(1H, s). 19 A 41 mp 177.6-178.2° C.; IR ν_(max)(Nujol)/cm⁻¹ 3511, 3406, 3289, 3254, 3164, 3132, 2924, 2854, 1723, 1636, 1600, 1588, 1549, 1467 and 1403; NMR δ_(H)(400MHz, DMSO) 1.23-1.34(1H, m), 1.36-1.54(4H, m), 1.58-1.68(1H, m), 1.73-1.81(2H, m), 1.94-2.06(2H, m), 3.73-3.84(1H, m), 6.75-6.81(1H, m), 6.91(1H, s), 7.76(1H, d, J 2.6Hz), 7.99(1H, s), 8.44(1H, s) and 8.80(1H, d, J 7.5Hz). 20 A 24 mp >300° C. dec.; IR ν_(max)(Nujol)/cm⁻¹ 3368, 3323, 3217, 3140, 3128, 2956, 2925, 2855, 1750, 1641, 1590, 1565, 1468, 1400, 1371, 1274 and 995; NMR δ_(H)(400MHz, DMSO) 1.04(6H, d, J 6.3Hz), 2.03-2.19(1H, m), 4.23(2H, d, J 7.0Hz), 6.77-6.81(1H, m), 6.85(2H, s), 7.74(1H, d, J 3.6Hz), 8.01(1H, s) and 8.46(1H, s); Anal. Calcd for C₁₄H₁₅N₅O₃: C, 55.81; H, 5.02; N, 23.23. Found: C, 55.84; H, 5.08; N, 23.24. 21 A 73 mp 295° C. dec.; IR ν_(max)(Nujol)/cm⁻¹ 3517, 3310, 3269, 3190, 3127, 3082, 2924, 2854, 1734, 1644, 1627, 1603, 1561, 1468 and 1369; NMR δ_(H)(400MHz, CDCl₃) 1.52(9H, s), 5.14(2H, s), 6.62-6.70(1H, m), 7.72-7.74(1H, m), 7.86(1H, d, J 3.5Hz), 8.47(1H, s) and 8.59(1H, s); Anal. Calcd for C₁₄H₁₆N₆O₂: C, 55.99; H, 5.37; N, 27.97. Found: C, 55.78; H, 5.35; N, 27.79. 22 A 75 mp >300° C. dec.; IR ν_(max)(Nujol)/cm⁻¹ 3499, 3298, 3179, 3117, 2924, 2854, 1790, 1635, 1589, 1373, 1302 and 1193; NMR δ_(H)(400MHz, DMSO) 6.78-6.82(1H, m), 6.96(2H, s), 7.37-7.44(1H, m), 7.44-7.50(2H, m), 7.50-7.59(2H, m), 7.75-7.77(2H, m), 8.02-8.03(1H, m) and 8.65(1H, s); Anal. Calcd for C₁₆H₁₁N₅O₃.0.25 H₂O: C, 58.99; H, 3.56; N, 21.50. Found: C, 58.79; H, 3.32; N, 21.82. 23 A 26 mp >330° C. dec.; IR ν_(max)(Nujol)/cm⁻¹ 2924, 2854, 1678, 1613, 1597, 1568, 1355, 1288 and 751; NMR δ_(H)(400MHz, DMSO) 6.88-6.93(1H, m), 7.09(1H, t, J 7.4Hz), 7.41(2H, t, J 8.1Hz), 7.75(1H, d, J 8.0Hz), 7.92(1H, s), 8.24(1H, s), 8.48(1H, s), 10.02(1H, s), 12.35(1H, s) and 13.42(1H, s); Anal. Calcd for C₁₆H₁₂N₆O₂: C, 60.00; H, 3.78; N, 26.22. Found: C, 59.60; H, 3.75; N, 26.01; M/Z 321(M+H)⁺. 24 A 74 mp >280° C. dec.; IR ν_(max)(Nujol)/cm⁻¹ 3510, 3292, 3161, 3112, 3053, 2955, 2925, 2854, 1749, 1725, 1645, 1603, 1591, 1567, 1468, 1401, 1372 and 748; NMR δ_(H)(400MHz, DMSO) 1.26(3H, t, J 7.2Hz), 3.38-3.49(2H, m), 6.78-6.83(1H, m), 7.05(2H, s), 7.77(1H, d, J 3.5Hz), 8.02-8.04(1H, s), 8.48(1H, s) and 8.86(1H, t, J 5.5Hz); Anal. Calcd for C₁₂H₁₂N₆O₂: C, 52.94; H, 4.44; N, 30.85. Found: C, 52.94; H, 4.59; N, 30.65. 25 A 21 mp >300° C. dec.; IR ν_(max)(Nujol)/cm⁻¹ 3392, 3315, 3193, 3135, 3114, 2924, 2854, 1728, 1641, 1601, 1557, 1509, 1479, 1468, 1405, 1377, 1270, 1240 and 763; NMR δ_(H)(400MHz, DMSO) 6.80-6.85(1H, m), 7.23(1H, t, J 7.4Hz), 7.31(2H, s), 7.48(2H, t, J 8.0Hz), 7.78-7.85(3H, m), 8.04-8.07(1H, m), 8.60(1H, s) and 11.13(1H, s); Anal. Calcd for C₁₆H₁₂N₆O₂.0.5 H₂O: C, 58.36; H, 3.98; N, 25.52. Found: C, 58.38; H, 3.70; N, 25.61. 26 G 84 mp >300° C. dec.; IR ν_(max)(Nujol)/cm⁻¹ 3515, 3279, 3187, 3131, 2924, 2854, 1725, 1631, 1600, 1552, 1465, 1400 and 1373; NMR δ_(H)(400MHz, DMSO) 4.66(2H, d, J 6.2Hz), 6.79-6.83(1H, m), 7.06(2H, s), 7.29-7.45(5H, m), 7.78(1H, d, J 3.5Hz), 8.03(1H, s), 8.53(1H, s) and 9.34(1H, t, J 6.2Hz); Anal. Calcd for C₁₇H₁₄N₆O₂.0.1 H₂O: C, 60.74; H, 4.26; N, 25.00. Found: C, 60.94; H, 4.25; N, 24.67. 27 H 53 mp 238.7-239.2° C.; IR ν_(max)(Nujol)/cm⁻¹ 3500, 3343, 3221, 3135, 3064, 2925, 2854, 1628, 1593, 1566, 1478, 1383, 1349, 1146 and 1065; NMR δ_(H)(400MHz, DMSO) 1.29(9H, s), 6.65-6.79(1H, m), 7.05(2H, s), 7.69(1H, d, J 3.5Hz), 7.73(2H, d, J 9.1Hz), 7.98-8.01(1H, m), 8.19(2H, d, J 8.6Hz) and 8.53(1H, s); Anal. Calcd for C₁₉H₁₉N₅O₃S.0.1 H₂O: C, 57.16; H, 4.85; N, 17.54. Found: C, 57.04; H, 4.86; N, 17.22. 28 H 65 mp >300° C. dec.; IR ν_(max)(Nujol)/cm⁻¹ 3497, 3283, 3158, 3129, 2931, 2854, 1720, 1627, 1593, 1467, 1392, 1360, 1259, 1180 and 746; NMR δ_(H)(400MHz, DMSO) 1.23-1.35(1H, m), 1.39-1.58(4H, m), 1.69-1.82(3H, m), 1.95-2.04(2H, m), 3.94-4.03(1H, m), 6.77-6.80(1H, m), 6.91(2H, m), 7.74(1H, d, J 3.5Hz), 7.99-8.09(1H, m) and 8.56(1H, s). 29 I 62 mp >300° C. dec.; IR ν_(max)(Nujol)/cm⁻¹ 3414, 3312, 3206, 3137, 3118, 2922, 2854, 1681, 1629, 1588, 1565, 1464, 1403, 1368 and 1194; NMR δ_(H)(400MHz, DMSO) 1.82-2.01(4H, m), 3.49-3.63(4H, m), 6.76-6.80(1H, m), 6.81(2H, s), 7.72-7.77(1H, m), 8.06(1H, s) and 8.31(1H, s). 30 G 92 mp >300° C. dec.; IR ν_(max)(Nujol)/cm⁻¹ 3550, 3378, 3309, 3242, 3139, 3054, 2924, 2854, 1715, 1640, 1603, 1588, 1543, 1465 and 1377; NMR δ_(H)(400MHz, DMSO) 1.32(6H, d, J 6.6Hz), 3.98-4.10(1H, m), 6.78-6.81(1H, m), 7.08(2H, s), 7.76(1H, d, J 3.5Hz), 8.01-8.04(1H, m), 8.47(1H, s) and 8.79(1H, d, J 7.4Hz); Anal. Calcd for C₁₃H₁₄N₆O₂.0.9 H₂O: C, 51.62; H, 5.26; N, 27.78. Found: C, 51.80; H, 5.04; N, 27.51. 31 A 38 mp 177.4-177.8° C.; IR ν_(max)(Nujol)/cm⁻¹ 3304, 3126, 3106, 2926, 2854, 1726, 1597, 1567, 1548, 1465, 1377 and 768; NMR δ_(H)(400MHz, DMSO) 1.29-1.41(1H, m), 1.44-1.53(4H, m), 1.60-1.69(1H, m), 1.75-1.85(2H, m), 2.00-2.10(2H, m), 3.89-4.00(1H, m), 6.67-6.72(1H, m), 7.80-7.82(1H, m) and 7.94(1H, d, J 3.5Hz). 33 H 17 mp 175.4-176.1° C.; IR ν_(max)(Nujol)/cm⁻¹ 3497, 3294, 3173, 3122, 2924, 2854, 1729, 1623, 1595, 1463, 1392, 1376 and 1359; NMR δ_(H)(400MHz, CDCl₃) 1.09(6H, d, 6.5Hz), 2.27-2.42(1H, m), 3.24(2H, d, J 6.3Hz), 5.16(1H, s), 6.62-6.66(1H, m), 7.70-7.73(1H, m), 7.82(1H, d, J 3.5Hz) and 8.48(1H, s); Anal. Calcd for C₁₄H₁₅N₅O₂: C, 58.94; H, 5.30; N, 24.54. Found: C, 58.84; H, 5.30; N, 24.19. 34 H 14 mp >300° C. dec.; NMR δ_(H)(400MHz, CDCl₃) 2.94(3H, s), 5.21(2H, s), 6.62-6.69(1H, m), 7.72(1H, s), 7.83(1H, d, J 3.6Hz) and 8.48(1H, s). 35 G 82 mp 175.5° C.; IR ν_(max)(Nujol)/cm⁻¹ 3282, 3131, 3116, 3033, 2924, 2854, 1735, 1587, 1576, 1538, 1478, 1462, 1375, 1294 and 1201; NMR δ_(H)(400MHz, CDCl₃) 2.35(3H, s), 4.69(2H, d, J 5.5Hz), 6.63-6.67(1H, m), 7.33-7.44(5H, m), 7.77-7.78(1H, m), 7.84(1H, d, J 3.4Hz), 8.65(1H, s) and 8.96-9.03(1H, s); Anal. Calcd for C₁₈H₁₅N₅O₂S: C, 59.17; H, 4.14; N, 19.16. Found: C, 59.00; H, 4.14; N, 18.95. 36 G 100 IR ν_(max)(Nujol)/cm⁻¹ 3399, 3317, 3204, 1717, 1643, 1603, 1557, 1510, 1403, 1268 and 1232; NMR δ_(H)(400MHz, DMSO) 0.94(3H, t, J, 7.3Hz), 1.39(2H, sextet, J 7.4Hz), 1.61(2H, quintet, J 7.3Hz), 3.38(2H, q, J 6.5Hz), 6.78(1H, dd, J 1.5, 3.5Hz), 7.02(2H, br s), 7.74(1H, dd, J 1.0, 3.5Hz), 8.00(1H, dd, J 1.0, 1.5Hz), 8.46(1H, s) and 8.83(1H, t, J 5.4Hz); Retention time: 4.12min 37 G 100 NMR δ_(H)(400MHz, DMSO) 3.74(3H, s), 4.55(2H, d, J 5.9Hz), 6.78(1H, dd, J 1.5, 3.5Hz), 6.93(2H, d, J 8.5Hz), 7.01(2H, br s), 7.33(2H, d, J 8.5Hz), 7.75(1H, dd, J 1.0, 3.5Hz), 8.01(1H, m), 8.49(1H, s) and 9.23(1H, t, J 6.3Hz); Retention time: 4.62min 38 G 97 NMR δ_(H)(400MHz, DMSO) 2.29(3H, s), 4.58(2H, d, J 6.1Hz), 6.78(1H, dd, J 1.5, 3.5Hz), 7.01(2H, br s), 7.17(2H, d, J 8.0Hz), 7.29(2H, d, J 8.0Hz), 7.75(1H, dd, J 1.0, 3.5Hz), 8.01(1H, dd, J 1.0, 1.5Hz), 8.50(1H, s) and 9.26(1H, t, J 6.3Hz); Retention time: 5.55min 39 G 100 NMR δ_(H)(400MHz, DMSO) 4.69(2H, d, J 6.6Hz), 6.79(1H, dd, J 1.5, 3.5Hz), 7.00(2H, br s), 7.36(2H, m), 7.51(2H, m), 7.76(1H, dd, J 1.0, 3.5Hz), 8.02(1H, m), 8.50(1H, s) and 9.41(1H, t, J 6.4Hz); Retention time: 5.63min 40 G 96 NMR δ_(H)(400MHz, DMSO) 6.77(1H, dd, J 1.5, 3.5Hz), 7.00(2H, br s), 7.42-7.68(7H, m), 7.75(1H, dd, J 1.0, 3.5Hz), 8.01(1H, dd, J 1.0, 1.5Hz), 8.22(1H, s) and 9.21(1H, s); Retention time: 6.94min; (80:50). 41 G 70 NMR δ_(H)(400MHz, DMSO) 0.86(3H, t, J 6.8Hz), 1.22-1.39(10H, m), 3.37(2H, q, J 6.7Hz), 6.78(1H, dd, J 1.5, 3.5Hz), 7.02(2H, br s), 7.74(1H, dd, J 1.0, 3.5Hz), 8.01(1H, dd, J 1.0, 1.5Hz), 8.46(1H, s) and 8.84(1H, t, J 5.7Hz); Retention time: 6.96min 42 G 100 NMR δ_(H)(400MHz, DMSO) 2.44(3H, s), 6.81(1H, dd, J 2.0, 3.5Hz), 7.10(2H, br s), 7.16(2H, m), 7.29(1H, m), 7.34(1H, m), 7.78(1H, m), 8.03(1H, m), 8.60(1H, s) and 10.64(1H, s); Retention time: 3.82min 43 G 90 NMR δ_(H)(400MHz, DMSO) 2.37(3H, s), 6.80(1H, dd, J 1.5, 3.5Hz), 7.02(1H, m), 7.32(3H, m), 7.61(2H, m), 7.77(1H, br d, J 3.5Hz), 8.03(1H, d, J 1.0Hz), 8.57(1H, s) and 11.05(1H, s); Retention time: 6.54min 44 G 91 NMR δ_(H)(400MHz, DMSO) 6.81(1H, dd, J 1.5, 3.5Hz), 7.03(2H, br s), 7.07(1H, m), 7.27(1H, m), 7.46(1H, m), 7.79(1H, dd, J 1.0, 3.5Hz), 8.04(1H, m), 8.27(1H, m), 8.62(1H, s) and 11.12(1H, s); Retention time: 6.65min 45 G 87 NMR δ_(H)(400MHz, DMSO) 1.60(3H, d, J 7.0Hz), 5.11(1H, quintet, J 7.2Hz), 6.78(1H, dd, J 1.5, 3.5Hz), 7.13(2H, br s), 7.29(1H, m), 7.38(2H, m), 7.45(2H, m), 7.75(1H, dd, J 1.0, 3.5Hz), 8.02(1H, m), 8.45(1H, s) and 9.34(1H, d, J 8.0Hz); Retention time: 5.11min 46 G 91 NMR δ_(H)(400MHz, DMSO) 1.60(3H, d, J 7.0Hz), 5.12(1H, quintet, J 7.1Hz), 6.79(1H, dd, J 1.5, 3.5Hz), 7.13(2H, br s), 7.29(1H, m), 7.38(2H, m), 7.46(2H, m), 7.75(1H, dd, J 1.0, 3.5Hz), 8.01(1H, dd, J 1.0, 1.5Hz), 8.44(1H, s) and 9.34(1H, d, J 8.0Hz); Retention time: 5.14min 47 G 96 NMR δ_(H)(400MHz, DMSO) 2.30(3H, s), 4.59(2H, d, J 6.2Hz), 6.79(1H, dd, J 2.0, 3.5Hz), 7.02(2H, br s), 7.09(1H, m), 7.20(2H, m), 7.26(1H, m), 7.75(1H, br d, J 3.5Hz), 8.01(1H, m), 8.50(1H, s) and 9.28(1H, d, J 6.1Hz); Retention time: 5.63min 48 G 89 NMR δ_(H)(400MHz, DMSO) 2.32(3H, s), 6.80(1H, dd, J 2.0, 3.5Hz), 7.25(2H, d, J 8.0Hz), 7.28(2H, br s), 7.68(2H, d, J 8.0Hz), 7.77(1H, br d, J 3.1Hz), 8.03(1H, m), 8.57(1H, s) and 11.02(1H, s); Retention time: 6.66min 49 G 100 NMR δ_(H)(400MHz, DMSO) 3.99(3H, s), 6.80(1H, dd, J 1.5, 3.5Hz), 6.89(2H, br s), 7.01(1H, m), 7.17(2H, m), 7.79(1H, dd, J 1.0, 3.5Hz), 8.04(1H, m), 8.16(1H, m), 8.60(1H, s) and 10.98(1H, s); Retention time: 6.28min 50 G 77 NMR δ_(H)(400MHz, DMSO) 3.78(3H, s), 6.80(1H, dd, J 1.5, 3.5Hz), 7.02(2H, d, J 9.1Hz), 7.26(2H, br s), 7.69(2H, d, J 9.0Hz), 7.77(1H, dd, J 1.0, 3.5Hz), 8.03(1H, dd, J 1.0, 1.5Hz), 8.56(1H, s) and 10.93(1H, s); Retention time: 5.70min 51 G 100 NMR δ_(H)(400MHz, DMSO) 6.38(2H, br s), 6.80(1H, dd, J 2.0, 3.5Hz), 7.52(2H, d, J 9.0Hz), 7.77(1H, br d, J 3.5Hz), 7.84(2H, m, J 9.0Hz), 8.03(1H, m), 8.58(1H, s) and 11.21(1H, s); Retention time: 7.19min 52 G 62 NMR δ_(H)(400MHz, DMSO) 0.90(3H, t, J 7.1Hz), 1.35(4H, m), 1.63(2H, quintet, J 7.2Hz), 3.37(2H, q, J 6.7Hz), 6.78(1H, dd, J 1.5, 3.5Hz), 7.02(2H, br s), 7.74(1H, dd, J 0.5, 3.5Hz), 8.01(1H, m), 8.46(1H, s) and 8.84(1H, t, J 5.8Hz); Retention time: 5.27min 53 G 81 NMR δ_(H)(400MHz, DMSO) 0.83(3H, t, J 6.8Hz), 1.19-1.38(18H, m), 1.62(2H, quintet, J 7.0Hz), 3.37(2H, q, J 6.4Hz), 6.78(1H, dd, J 1.5, 3.5Hz), 7.02(2H, br s), 7.75(1H, dd, J 0.5, 3.5Hz), 8.01(1H, m), 8.46(1H, s) and 8.84(1H, t, J 5.9Hz); Retention time: 10.76min 54 K 57 IR ν_(max)(Nujol)/cm⁻¹ 3431, 3384, 3334, 3220, 3122, 1665, 1648, 1587, 1564, 1302, 1210 and 1130; NMR δ_(H)(400MHz, CDCl₃) 1.01(2H, m), 1.17-1.32(4H, m), 1.66-1.82(7H, m), 4.14(2H, t, J 7.5Hz), 6.32(2H, br s), 6.69(1H, m), 7.81(1H, m), 7.89(1H, m) and 7.99(1H, m); M/Z 312(M+H)⁺; Retention time: 5.09min 55 G 63 IR ν_(max)(Nujol)/cm⁻¹ 3320, 3218, 3109, 3029, 2926, 2854, 1734, 1601, 1587, 1550, 1464 and 1375; NMR δ_(H)(400MHz, DMSO) 3.31(6H, s), 4.66(2H, d, J 5.5Hz), 6.80-6.82(1H, m), 7.30-7.36(1H, m), 7.38-7.43(2H, m), 7.44-7.50(2H, m), 7.80(1H, d, J 3.5Hz), 8.05-8.07(1H, m), 8.53(1H, s) and 9.11(1H, t, J 5.0Hz); Anal. Calcd for C₁₉H₁₈N₆O₂.0.25 H₂O: C, 62.20; H, 5.08; N, 22.91. Found: C, 62.42; H, 5.01; N, 22.58. 56 H 86 mp 212.6-213° C.; IR ν_(max)(Nujol)/cm⁻¹ 3138, 2925, 2854, 1601, 1555, 1463, 1372, 1352, 1183, 670 and 584; NMR δ_(H)(400MHz, DMSO) 2.41(3H, s), 3.21(6H, s), 6.76-6.80(1H, m), 7.53(2H, d, J 7.9Hz), 7.72(1H, d, J 3.5Hz), 8.02-8.04(1H, m), 8.12-8.16(2H, m) and 8.54(1H, s); Anal. Calcd for C₁₈H₁₇N₅O₃S: C, 56.39; H, 4.47; N, 18.26. Found: C, 56.20; H, 4.48; N, 18.23. 57 K 21 NMR δ_(H)(4.00MHz, CDCl₃) 4.89(2H, dd, J 1.5, 6.0Hz), 5.09(2H, br s), 6.37(1H, dt, J 6.0, 16.0Hz), 6.59(1H, dt, J 1.5, 16.0Hz), 6.64(1H, dd, J 1.5, 3.5Hz), 7.28-7.38(5H, m), 7.72(1H, dd, J 1.0, 1.5Hz), 7.82(1H, dd, J 1.0, 3.5Hz) and 7.84(1H, s); M/Z 318(M+H)⁺; Retention time: 3.82min 58 K 18 NMR δ_(H)(400MHz, CDCl₃) 1.74(3H, m), 4.65(2H, m), 5.06(2H, br s), 5.71(2H, m), 6.63(1H, dd, J 1.5, 3.5Hz), 7.71(1H, dd, J 1.0, 1.5Hz), 7.78(1H, s) and 7.80(1H, dd, J 1.0, 3.5Hz); M/Z 256(M+H)⁺; Retention time: 1.19min 59 K 40 M/Z 258(M+H)⁺; Retention time: 1.40min 60 K 20 M/Z 270(M+H)⁺; Retention time: 1.43min 61 K 18 M/Z 244(M+H)⁺; Retention time: 0.87min 62 K 34 NMR δ_(H)(400MHz, CDCl₃) 1.68(2H, quintet, J 7.5Hz), 1.92(2H, quintet, J 7.5Hz), 2.67(2H, t, J 7.5Hz), 4.12(2H, t, J 7.1Hz), 5.63(2H, br s), 6.67(1H, br s), 7.12-7.30(5H, m), 7.77(2H, m) and 7.89(1H, m); Retention time: 4.60min 63 K 43 NMR δ_(H)(400MHz, CDCl₃) 3.79(2H, t, J 5.0Hz), 4.30(2H, t, J 4.8Hz), 4.51(2H, s), 6.17(2H, br s), 6.69(1H, dd, J 1.5, 3.5Hz), 7.20-7.32(5H, m), 7.80(1H, m), 7.98(1H, m) and 8.00(1H, s); Retention time: 1.88min 64 K 19 NMR δ_(H)(400MHz, CDCl₃) 0.99(6H, d, J 6.5Hz), 1.62(1H, septet, J 6.6Hz), 1.78(2H, q, J 7.4Hz), 4.13(2H, t, J 7.2Hz), 5.15(2H, br s), 6.63(1H, m), 7.71(1H, m) and 7.80(2H, m); Retention time: 2.21min 65 K 31 NMR δ_(H)(400MHz, CDCl₃) 1.82(6H, d, J 6.6Hz), 4.68(2H, d, J 7.0Hz), 5.41(1H, t, J 7.0Hz), 6.24(2H, br s), 6.69(1H, m), 7.80(1H, m), 7.87(1H, m) and 7.98(1H, m); Retention time: 1.82min 66 K 22 NMR δ_(H)(400MHz, CDCl₃) 5.29(2H, s), 5.85(2H, br s), 6.63(1H, m), 7.33-7.46(4H, m), 7.57-7.72(3H, m) and 8.22(1H, s); Retention time: 1.87min 67 K 21 NMR δ_(H)(400MHz, CDCl₃) 5.27(2H, s), 5.97(2H, br s), 6.55(1H, m), 7.29-7.60(6H, m) and 8.21(1H, s); Retention time: 3.93min 68 K 23 NMR δ_(H)(400MHz, CDCl₃) 2.26(2H, quintet, J 7.2Hz), 2.71(2H, t, J 7.4Hz), 4.14(2H, t, J 7.3Hz), 6.72(1H, m), 6.83(2H, br s), 7.15-7.33(5H, m), 7.86(1H, m), 7.92(1H, m) and 8.06(1H, m); Retention time: 3.48min 69 X 55 mp 184.3-184.5° C.; IR ν_(max)(Nujol)/cm⁻¹ 3458, 3316, 3200, 3069, 2955, 2924, 2854, 1749, 1728, 1631, 1606, 1592, 1462 and 1210; NMR δ_(H)(400MHz, DMSO) 1.24(3H, t, J 7.1Hz), 4.19(2H, q, J 7.1Hz), 5.01(2H, s), 6.61(2H, s), 6.75-6.79(1H, m), 7.75(1H, d, J 2.5Hz), 7.98(1H, s) and 8.11(1H, s); Anal. Calcd for C₁₈H₁₇N₅O₃S: C, 56.39; H, 4.47; N, 18.26. Found: C, 56.20; H, 4.48; N, 18.23. 70 L 19 IR ν_(max)(Nujol)/cm⁻¹ 3139, 3109, 2924, 2854, 1740, 1610, 1583, 1561, 1547, 1403, 1235 and 1114; NMR δ_(H)(400MHz, DMSO) 1.25(6H, d, J 6.1Hz), 3.21(6H, s), 5.00(2H, s), 6.77-6.80(1H, m), 7.76(1H, d, J 3.5Hz), 7.99-8.03(1H, m) and 8.14(1H, s); Anal. Calcd for C₁₈H₁₇N₅O₃S: C, 56.39; H, 4.47; N, 18.26. Found: C, 56.20; H, 4.48; N, 18.23. 71 B 47 mp 180.6-181.8° C.; IR ν_(max)(Nujol)/cm⁻¹ 3387, 3139, 3116, 2925, 2854, 1744, 1611, 1588, 1559, 1464, 1401, 1376, 1220, 1008 and 764; NMR δ_(H)(400MHz, CDCl₃) 1.28(3H, t, J 7.0Hz), 4.26(2H, q, J 7.0Hz), 4.86(2H, s), 6.58-6.62(1H, m), 7.65-7.67(1H, m), 7.71-7.73(1H, m) and 7.79(1H, s); Anal. Calcd for C₁₅H₁₇N₅O₃: C, 57.14; H, 5.43; N, 22.20. Found: C, 56.88; H, 5.43; N, 22.05. 72 A 12 mp 314° C.; IR ν_(max)(Nujol)/cm⁻¹ 3142, 3106, 3064, 2924, 2854, 1736, 1587, 1567, 1487, 1402, 1347, 1230 and 768; NMR δ_(H)(400MHz, CDCl₃) 1.31(3H, t, J 7.0Hz), 4.30(2H, q, J 7.0Hz), 5.10(2H, s), 6.56-6.59(1H, m), 6.66-6.68(1H, m), 7.40(1H, d, J 3.7Hz), 7.64-7.65(1H, m), 7.79-7.81(1H, m), 7.89(1H, d, J 3.5Hz) and 8.15(1H, s); Anal. Calcd for C₁₇H₁₄N₄O₄: C, 60.35; H, 4.17; N, 16.56. Found: C, 59.91; H, 4.25; N, 16.36. 73 M 72 mp >300° C. dec.; IR ν_(max)(Nujol)/cm⁻¹ 3320, 3129, 3107, 2924, 2854, 2776, 1908, 1690, 1636, 1597, 1465, 1383, 1312, 782, 768, 686 and 676; NMR δ_(H)(400MHz, DMSO) 4.90(2H, s), 6.60(2H, s), 6.75-6.79(1H, m), 7.73-7.75(1H, m), 7.97-7.98(1H, s), 8.11(1H, s), 13.02-13.48(1H, s); Anal. Calcd for C₁₁H₉N₅O₃: C, 50.97; H, 3.50; N, 27.00. Found: C, 50.75; H, 3.53; N, 26.80. 74 N 67 mp 79.6° C. dec; IR ν_(max)(Nujol)/cm⁻¹ 3094, 2924, 2855, 1600, 1466, 1380, 1248, 1092 and 839; NMR δ_(H)(400MHz, CDCl₃) −0.04(9H, s), 0.95(2H, m), 3.65(2H, m), 4.10(3H, s), 5.60(2H, s), 6.65(1H, dd, J 3.5, 1.7Hz), 7.78(2H, m) and 8.08(1H, s). Retention time: 5.82min (80:50) 75 C 43 IR ν_(max)(Nujol)/cm⁻¹ 2924, 2854, 1636, 1599, 1569, 1466, 1357 and 756; NMR δ_(H)(400MHz, DMSO) 3.99(3H, s), 6.81(1H, dd, J 3.5, 1.7Hz), 7.85(1H, d, J 3.5Hz), 8.05(1H, m), 8.38(1H, s) and 13.3(1H, br s); M/Z 217(M+H)⁺; Retention time: 0.81min (80:50) 77 G 79 mp >200° C. dec; IR ν_(max)(Nujol)/cm⁻¹ 3458, 3360, 2925, 1721, 1611, 1549, 1465, 1386, 1046 and 702; NMR δ_(H)(400MHz, DMSO) 4.64(2H, d, J 6.5Hz), 6.97(2H, br s), 7.23-7.44(6H, m), 7.88(1H, dd, J 5.0, 1.5Hz) 8.53(1H, s) 8.55(1H, dd, J 3.5, 1.0Hz) and 9.33(1H, br t, J 6.0Hz); Retention time: 6.08min 78 A 5 mp >250° C. dec; IR ν_(max)(Nujol)/cm⁻¹ 3332, 3215, 3144, 2925, 1741, 1651, 1576, 1378, 1292, 1143, 993 and 713; NMR δ_(H)(400MHz, DMSO) 1.69(9H, s), 5.22(2H, br. s), 7.22(1H, dd, J 5.0, 3.5Hz), 7.57(1H, dd, J 5.0, 1.0Hz), 8.10(1H, s) and 8.58(1H, dd, J 4.5, 1.5Hz); Retention time: 3.95min 79 G 59 NMR δ_(H)(400MHz, DMSO) 4.61(2H, d, J 5.9Hz), 6.78(1H, dd, J 1.5, 3.5Hz), 7.01(2H, br s), 7.22(2H, m), 7.45(2H, m), 7.75(1H, dd, J 1.0, 3.5Hz), 8.01(1H, dd, J 1.0, 1.5Hz), 8.50(1H, s) and 9.31(1H, t, J 6.2Hz); Retention time: 5.07min 80 G 100 NMR δ_(H)(400MHz, DMSO) 4.63(2H, d, J 6.1Hz), 6.78(1H, dd, J 1.5, 3.5Hz), 6.99(2H, br s), 7.41(1H, dd, J 2.0, 8.5Hz), 7.63(1H, d, J 8.5Hz), 7.69(1H, d, J 2.0Hz), 7.75(1H, br d, J 3.5Hz), 8.01(1H, m), 8.49(1H, s) and 9.35(1H, t, J 6.1Hz); Retention time: 7.12min 81 K 66 NMR δ_(H)(400MHz, CDCl₃) 3.16(2H, t, J 7.0Hz), 4.35(2H, t, J 7.0Hz), 5.05(2H, br s), 6.62(1H, m), 7.09(2H, m), 7.22-7.31(3H, m), 7.40(1H, s), 7.70(1H, m) and 7.76(1H, m); Retention time: 2.13min 82 K 10 NMR δ_(H)(400MHz, CDCl₃) 1.95(3H, d, J 7.0Hz), 5.03(2H, br s), 5.81(1H, q, J 7.0Hz), 6.63(1H, dd, J 1.5, 3.5Hz), 7.04(2H, m), 7.30(2H, m), 7.71(1H, m), 7.75(1H, m) and 7.79(1H, m); Retention time: 2.94min 83 K 48 NMR δ_(H)(400MHz, CDCl₃) 1.23(6H, d, J 6.6Hz), 2.89(1H, septet, J 6.9Hz), 5.06(2H, br s), 5.25(2H, s), 6.63(1H, dd, J 1.5, 3.5Hz), 7.21(4H, s), 7.71(1H, dd, J 1.0, 1.5Hz), 7.74(1H, s) and 7.79(1H, br d, J 3.5Hz); Retention time: 5.23min 84 K 12 NMR δ_(H)(400MHz, CDCl₃) 5.06(2H, br s), 5.19(2H, s), 6.64(1H, dd, J 1.5, 3.5Hz), 6.99-7.16(3H, m), 7.72(1H, m), 7.75(1H, s) and 7.80(1H, br d, J 3.5Hz); Retention time: 3.22min 85 P 31 mp 289.1-289.7° C.; IR ν_(max)(Nujol)/cm⁻¹ 3499, 3477, 3314, 3264, 3199, 3139, 3076, 2926, 2854, 1673, 1662, 1634, 1606, 1590, 1467 and 750; NMR δ_(H)(400MHz, DMSO) 5.03(2H, s), 6.55(2H, s), 6.76-6.79(1H, m), 7.09(1H, t, J 7.5Hz,) 7.34(2H, t, J 8.1Hz), 7.60(2H, d, J 7.6Hz), 7.76(1H, d, J 4.0Hz), 7.97-7.99(1H, s), 8.12(1H, s) and 10.43(1H, s); Anal. Calcd for C₁₇H₁₄N₆O₂.0.4 H₂O: C, 59.78; H, 4.37; N, 24.61. Found: C, 59.92; H, 4.08; N, 24.36. 86 Q 66 mp 287.2-287.8° C.; IR ν_(max)(Nujol)/cm⁻¹ 3479, 3464, 3279, 3182, 3076, 2924, 2854, 1656, 1631, 1608, 1539, 1567 and 1464; NMR δ_(H)(400MHz, DMSO) 4.34(2H, d, J 5.9Hz), 4.86(2H, s), 6.53(2H, s), 6.75-6.78(1H, m), 7.24-7.39(5H, m), 7.75(1H, d, J 3.0Hz), 7.97(1H, s), 8.09(1H, s) and 8.72(1H, t, J 5.8Hz). 87 Q 100 mp 321.5-321.6° C.; IR ν_(max)(Nujol)/cm⁻¹ 3379, 3296, 3220, 2924, 2854, 1689, 1662, 1593, 1463 and 1378; NMR δ_(H)(400MHz, DMSO) 4.75(2H, s), 6.53(2H, s), 6.74-6.78(1H, m), 7.29(1H, s), 7.69(1H, s), 7.74(1H, d, J 2.5Hz), 7.96-7.98(1H, m) and 8.05(1H, s). 88 Q 74 mp 283.6-283.7° C.; IR ν_(max)(Nujol)/cm⁻¹ 3368, 3332, 3215, 3098, 2925, 2854, 1648, 1585, 1566, 1467, 1408 and 1298; NMR δ_(H)(400MHz, DMSO) 1.83(2H, quin, J 6.8Hz), 1.98(2H, quin, J 6.8Hz), 3.34(2H, t, J 6.8Hz), 3.57(2H, t, J 6.8Hz), 4.97(2H, s), 6.52(2H, s), 6.75-6.78(1H, m), 7.75(1H, d, J 2.5Hz), 7.96-7.99(1H, m) and 8.01(1H, s); Anal. Calcd for C₁₅H₁₆N₆O₂.0.5 H₂O: C, 56.07; H, 5.33; N, 26.15. Found: C, 56.26; H, 5.08; N, 26.13. 89 Q 67 mp 290.2-291.6° C.; IR ν_(max)(Nujol)/cm⁻¹ 3558, 3471, 3324, 3113, 2924, 2854, 1664, 1626, 1598 and 1460; NMR δ_(H)(400MHz, DMSO) 2.64(3H, d, J 4.5Hz), 4.76(2H, s), 6.53(2H, s), 6.75-6.78(1H, m), 7.74(1H, d, J 3.2Hz), 7.96-7.98(1H, m), 8.06(1H, s) and 8.09-8.15(1H, m). 90 R 21 mp >200° C. dec; IR ν_(max)(Nujol)/cm⁻¹ 3499, 3394, 2925, 1628, 1598, 1455, 1378, 1249, 950, 878 and 628; NMR δ_(H)(400MHz, DMSO) 2.73(3H, s), 6.58(1H, br s), 8.24(1H, br s) and 12.76(1H, br s); M/Z 217(M+H)⁺; Retention time: 0.6min 91 G 72 mp >250° C. dec; IR ν_(max)(Nujol)/cm⁻¹ 3505, 3255, 3089, 2925, 1735, 1622, 1465, 1278, 887 and 725; NMR δ_(H)(400MHz, DMSO) 2.73(3H, s) 4.65(2H, d, J 6.0Hz), 7.18-7.45(5H, m), 8.56(1H, s) and 9.22(1H, br t, J 6.0Hz); Retention time: 1.99min 92 G 89 NMR δ_(H)(400MHz, DMSO) 2.96(2H, t, J 7.2Hz), 3.63(2H, q, J 6.9Hz), 6.78(1H, dd, J 1.9, 3.5Hz), 6.94(2H, br s), 7.17-7.30(5H, m), 7.74(1H, br d, J 3.5Hz), 8.01(1H, dd, J 1.0, 1.5Hz), 8.46(1H, s) and 8.92(1H, t, J 5.5Hz); Retention time: 4.89min 93 G 100 NMR δ_(H)(400MHz, DMSO) 4.66(2H, d, J 6.1Hz), 6.79(1H, dd, J 1.5, 3.5Hz), 7.00(2H, br s), 7.44(1H, m), 7.54(1H, m), 7.66(1H, m), 7.75(1H, dd, J 1.0, 3.5Hz), 8.01(1H, dd, J 1.0, 1.5Hz), 8.49(1H, s) and 9.40(1H, t, J 6.1Hz); Retention time: 7.06min 94 G 100 NMR δ_(H)(400MHz, DMSO) 1.74(3H, d, J 7.0Hz), 5.92(1H, quintet, J 7.0Hz), 6.79(1H, dd, J 1.5, 3.5Hz), 7.16(2H, br s), 7.47-7.68(5H, m), 7.76(1H, dd, J 1.0, 3.5Hz), 7.79-7.99(2H, m), 8.02(1H, dd, J 1.0, 1.5Hz), 8.45(1H, s) and 9.52(1H, t, J 8.2Hz); Retention time: 7.12min 95 G 85 NMR δ_(H)(400MHz, DMSO) 1.81(6H, s), 2.09(3H, s), 5.08(1H, m), 5.38(1H, m), 6.79(1H, dd, J 1.5, 3.5Hz), 7.09(2H, br s), 7.37(3H, m), 7.56(1H, m), 7.76(1H, dd, J 1.0, 3.5Hz), 8.02(1H, dd, J 1.0, 1.5Hz), 8.39(1H, s) and 9.33(1H, t, J 5.8Hz); Retention time: 7.14min 96 Q 84 mp >250° C. dec.; IR ν_(max)(Nujol)/cm⁻¹ 3462, 3279, 3212, 3097, 2924, 2854, 1660, 1591 and 1465; NMR δ_(H)(400MHz, DMSO) 3.13-3.24(2H, m), 3.41-3.49(2H, m), 4.73(1H, s), 4.79(2H, s), 6.53(2H, s), 6.74-6.79(1H, m), 7.74(1H, d, J 2.6Hz), 7.97(1H, s), 8.05(1H, s) and 8.24-8.34(1H, m). 97 Q 52 mp >270° C. dec.; IR ν_(max)(Nujol)/cm⁻¹ 3386, 3327, 3214, 3087, 2924, 2854, 1668, 1640, 1585, 1565, 1466, 1408 and 1376; NMR δ_(H)(400MHz, DMSO) 2.24(3H, s), 2.29-2.35(2H, m), 2.39-2.46(2H, m), 3.44-3.51(2H, m), 3.54-3.61(2H, m), 5.08(2H, s), 6.52(2H, s), 6.75-6.79(1H, m), 7.74(1H, d, J 3.7Hz), 7.97(1H, s) and 8.01(1H, s). 98 G 39 NMR δ_(H)(400MHz, DMSO) 3.74(2H, q, J 5.9Hz), 3.85(2H, t, J 6.0Hz), 6.78(1H, dd, J 1.5, 3.5Hz), 6.99(2H, br s), 7.75(1H, dd, J 1.0, 3.5Hz), 8.02(1H, dd, J 1.0, 1.5Hz), 8.49(1H, s) and 9.12(1H, t, J 5.8Hz); Retention time: 2.16min 99 G 80 NMR δ_(H)(400MHz, DMSO) 2.10(2H, quintet, J 6.7Hz), 3.52(2H, q, J 6.5Hz), 3.77(2H, t, J 6.5Hz), 6.78(1H, dd, J 2.0, 3.5Hz), 7.02(2H, br s), 7.74(1H, dd, J 1.0, 3.5Hz), 8.01(1H, dd, J 1.0, 2.0Hz), 8.47(1H, s) and 8.90(1H, t, J 5.7Hz); Retention time: 3.08min 100 G 70 NMR δ_(H)(400MHz, DMSO) 1.18(3H, t, J 6.9Hz), 2.70(2H, t, J 6.7Hz), 3.61(2H, q, J 6.5Hz), 4.10(2H, t, J 7.2Hz), 6.78(1H, dd, J 1.5, 3.5Hz), 6.96(2H, br s), 7.74(1H, br d, J 3.5Hz), 8.01(1H, dd, J 1.0, 1.5Hz), 8.47(1H, s) and 8.98(1H, t, J 5.8Hz); Retention time: 2.19min 101 G 46 NMR δ_(H)(400MHz, DMSO) 1.17(3H, t, J 7.0Hz), 3.19(1H, dd, J 8.5, 14.0Hz), 3.29(1H, dd, J 6.0, 14.0Hz), 4.15(2H, q, J 7.0Hz), 4.70(1H, m), 6.78(1H, dd, J 1.5, 3.5Hz), 7.03(2H, br s), 7.15-7.39(5H, m), 7.74(1H, dd, J 1.0, 3.5Hz), 8.02(1H, dd, J 1.0, 2.0Hz), 8.43(1H, s) and 9.23(1H, d, J 6.9Hz). 102 S 47 NMR δ_(H)(400MHz, CDCl₃) 3.34(2H, t, J 6.6Hz), 4.60(2H, t, J 6.7Hz), 5.05(2H, br s), 6.61(1H, dd, J 1.5, 3.5Hz), 6.98(1H, d, J 7.5Hz), 7.15(1H, m), 7.53(1H, m), 7.53(1H, s), 7.69(1H, m), 7.74(1H, dd, J 1.0, 3.5Hz) and 8.60(1H, m); Retention time: 0.76min 103 S 44 NMR δ_(H)(400MHz, DMSO) 3.36-3.42(10H, m), 4.49(2H, m), 6.90(1H, dd, J 1.5, 3.5Hz), 7.91(1H, br d, J 3.5Hz), 8.18(1H, m), 8.52(1H, s) and 9.62(2H, br s); Retention time: 0.80min, (50:20) 104 S 66 NMR δ_(H)(400MHz, CDCl₃) 1.44(2H, m), 1.57(4H, m), 2.45(4H, m), 2.69(2H, t, J 6.0Hz), 4.18(2H, t, J 6.0Hz), 5.02(2H, br s), 6.63(1H, m), 7.71(1H, m), 7.79(1H, m) and 7.99(1H, s); M/Z 313(M+H)⁺; Retention time: 3.69min, (50:20) 105 S 53 NMR δ_(H)(400MHz, CDCl₃) 1.78(4H, m), 2.58(4H, m), 2.90(2H, t, J 6.3Hz), 4.22(2H, t, J 6.2Hz), 5.03(2H, br s), 6.63(1H, dd, J 1.5, 3.5Hz), 7.71(1H, m), 7.79(1H, br d, J 3.5Hz) and 7.93(1H, s); Retention time: 1.50min, (50:20) 106 T 98 mp 161.7° C. dec; NMR δ_(H)(400MHz, CDCl₃) 5.36(2H, br s), 5.52(2H, s), 6.64(1H, dd, J 3.5, 1.7Hz), 7.35-7.75(5H, m), 7.72(1H, nm), 7.81(1H, m) and 8.26(1H, s); Retention time: 3.95min (80:50) 112 G 35 mp 139.3° C.; NMR δ_(H)(400MHz, CDCl₃) 3.99(3H, s), 4.70-4.71(2H, s, rotamers), 6.67(1H, dd, J 3.5, 1.7Hz), 7.27-7.44(5H, m), 7.79(1H, m), 7.84(1H, m), 8.66(1H, s) and 8.95(1H, br); Retention time: 5.13min (80:50) 113 S 37 NMR δ_(H)(400MHz, CDCl₃) 3.14(2H, t, J 6.8Hz), 4.33(2H, t, J 7.0Hz), 5.06(2H, br s), 6.63(1H, dd, J 1.5, 3.5Hz), 7.02(2H, d, J 8.1Hz), 7.25(2H, m), 7.41(1H, s), 7.72(1H, m) and 7.76(1H, br d, J 3.5Hz); Retention time: 4.02min 114 S 64 NMR δ_(H)(400MHz, CDCl₃) 2.91(6H, s), 3.04(2H, t, J 6.8Hz), 4.29(2H, t, J 6.8Hz), 5.05(2H, br s), 6.62(1H, dd, J 2.0, 3.5Hz), 6.65(2H, d, J 8.6Hz), 6.95(2H, d, J 8.7Hz), 7.40(1H, s), 7.70(1H, dd, J 1.0, 1.5Hz) and 7.76(1H, dd, J 1.0, 3.5Hz); Retention time: 2.58min 115 S 15 NMR δ_(H)(400MHz, CDCl₃) 4.30(2H, t, J 5.0Hz), 4.52(2H, t, J 5.0Hz), 5.08(2H, br s), 6.64(1H, dd, J 1.5, 3.5Hz), 6.87(2H, m), 6.96(1H, m), 7.27(2H, m), 7.71(1H, m), 7.80(1H, br d, J 3.5Hz) and 7.79(1H, s); Retention time: 2.37min 116 S 66 NMR δ_(H)(400MHz, CDCl₃) 1.01(2H, m), 1.21(4H, m), 1.69(4H, m), 1.89(1H, m), 3.39(2H, d, J 7.8Hz), 5.04(2H, br s), 6.64(1H, dd, J 1.5, 3.5Hz), 7.71(1H, m), 7.74(1H, s) and 7.79(1H, br d, J 3.5Hz); Retention time: 3.78min 117 S 84 NMR δ_(H)(400MHz, CDCl₃) 0.87(2H, m), 1.09-1.27(6H, m), 1.61-1.72(5H, m), 1.88(2H, quintet, J 7.0Hz), 4.08(2H, t, J 7.1Hz), 5.04(2H, br s), 6.64(1H, dd, J 2.0, 3.5Hz), 7.72(1H, dd, J 1.0, 2.0Hz), 7.78(1H, s) and 7.79(1H, dd, J 1.0, 3.5Hz); Retention time: 6.06min 118 I 20 NMR δ_(H)(400MHz, CDCl₃) 3.04(3H, s), 4.72(2H, br s), 5.18(2H, br s), 6.64(1H, dd, J 3.5, 1.7Hz), 7.29-7.42(5H, m), 7.72(1H, m), 7.83(1H, m), 8.10(1H, s); M/Z 349(M+H)⁺; Retention time: 1.66min (80:50) 119 Q 85 mp 238.3-238.4° C.; IR ν_(max)(Nujol)/cm⁻¹ 3444, 3325, 3181, 3083, 2925, 2855, 1651, 1696, 1591, 1567, 1523, 1467, 1414, 1376, 1355, 1300, 1182, 1017 and 754; NMR δ_(H)(400MHz, DMSO) 4.41(2H, d, J 5.4Hz), 4.88(2H, s), 6.53(2H, s), 6.72-6.77(1H, m), 7.25-7.31(1H, m), 7.36(2H, d, J 8.0Hz), 7.72(1H, d, J 3.6Hz), 7.75-7.81(1H, m), 7.94(1H, s), 8.08(1H, s), 8.51(1H, d, J 4.5Hz) and 8.80(1H, t, J 5.8Hz). 120 O 12 mp 310.0-310.3° C.; IR ν_(max)(Nujol)/cm⁻¹ 3322, 2925, 1636, 1586, 1464, 1378, 1297, 1026, 734 and 630; NMR δ_(H)(400MHz, DMSO) 6.53(2H, br s), 7.34(1H, t, J 7.5Hz), 7.45(1H, t, J 8.0Hz), 7.72(1H, d, J 8.5Hz), 7.83(1H, d, J 7.5Hz), 8.17(1H, br s), 8.21(1H, br s) and 12.78(1H, br s); Retention time: 1.48min 122 Q 46 mp 242.5-243.6° C.; IR ν_(max)(Nujol)/cm⁻¹ 3485, 3442, 3312, 3203, 3072, 2924, 2854, 1697, 1652, 1633, 1605, 1580, 1462, 1442, 1412 and 1303; NMR δ_(H)(400MHz, DMSO) 5.07(2H, s), 6.53(2H, s), 6.73-6.77(1H, m), 7.09-7.14(1H, m), 7.73(1H, d, J 2.8Hz), 7.77(1H, t, J 7.0Hz), 7.90-8.04(2H, m), 8.08(1H, s), 8.35(1H, d, J 4.0Hz) and 10.96(1H, s). 123 Q 57 mp 247.3-247.4° C.; IR ν_(max)(Nujol)/cm⁻¹ 3500, 3308, 3187, 3092, 3022, 2924, 2854, 1656, 1636, 1609, 1590, 1567 and 1466; NMR δ_(H)(400MHz, DMSO) 2.72(2H, t, J 7.3Hz), 3.24-3.35(2H, m), 4.73(2H, s), 6.49(2H, s), 6.71-6.77(1H, m), 7.15-7.23(3H, m), 7.25-7.32(2H, m), 7.71(2H, d, J 3.5Hz), 7.93-7.95(1H, m), 8.01(1H, s) and 8.29(1H, t, J 5.5Hz). 124 Q 46 mp 258.7-260.1° C.; IR ν_(max)(Nujol)/cm⁻¹ 3487, 3470, 3293, 3172, 3098, 2925, 2854, 1659, 1629, 1605, 1594, 1568, 1461 and 1409; NMR δ_(H)(400MHz, DMSO) 0.86(3H, t, J 7.6Hz), 1.39-1.48(2H, m), 3.05(2H, q, J 6.5Hz), 4.75(2H, s), 6.49(2H, s), 6.72-6.77(1H, m), 7.72(1H, d, J 3.5Hz), 7.93-7.96(1H, m), 8.04(1H, s) and 8.19(1H, t, J 5.5Hz). 125 S 12 NMR δ_(H)(400MHz, CDCl₃) 5.07(2H, br s), 5.27(2H, s), 6.64(1H, dd, J 1.5, 3.5Hz), 7.14(1H, m), 7.25-7.30(3H, m), 7.72(1H, m), 7.76(1H, s) and 7.80(1H, dd, J 1.0, 3.5Hz); Retention time: 2.66min 126 S 33 NMR δ_(H)(400MHz, CDCl₃) 2.32(3H, s), 5.07(2H, br s), 5.25(2H, s), 6.63(1H, dd, J 2.0, 3.5Hz), 7.06(2H, m), 7.13(1H, d, J 7.6Hz), 7.23(1H, d, J 7.6Hz), 7.71(1H, m), 7.74(1H, s) and 7.79(1H, dd, J 1.0, 3.5Hz); Retention time: 2.12min 127 S 17 NMR δ_(H)(400MHz, CDCl₃) 2.34(3H, s), 5.06(2H, br s), 5.24(2H, s), 6.63(1H, dd, J 2.0, 3.5Hz), 7.16(4H, m), 7.71(1H, dd, J 1.0, 2.0Hz), 7.73(1H, s) and 7.79(1H, dd, J 1.0, 3.5Hz); Retention time: 2.21min 128 G 53 mp >250° C. dec; IR ν_(max)(Nujol)/cm⁻¹ 3296, 3181, 2925, 1717, 1629, 1467, 1390, 1228 and 754; NMR δ_(H)(400MHz, DMSO) 4.66(2H, d, J 6.0Hz), 7.18(2H, br s), 7.21-7.51(7H, m), 7.74(1H, d, J 8.0Hz), 7.87(1H d, J 7.5Hz), 8.25(1H, s), 8.59(1H, s) and 9.30(1H, br t, J 6.0Hz); Retention time: 6.85min 129 O 36 mp >250° C. dec; IR ν_(max)(Nujol)/cm⁻¹ 3492, 3331, 3196, 2924, 1618, 1569, 1442, 1377, 1301, 1180, 1030 and 784; NMR δ_(H)(400MHz, DMSO) 6.39(2H, br s), 7.27(1H, d, J 4.0Hz), 8.12(1H, s), 8.33(1H, d, J 4.0Hz) and 12.68(1H, br s); Retention time: 2.74min 130 G 67 mp 194-195° C. dec; IR ν_(max)(Nujol)/cm⁻¹ 3460, 3360, 2923, 1722, 1608, 1465, 1386, 1218, 1013 and 792; NMR δ_(H)(400MHz, DMSO) 4.64(2H, d, J 6.0Hz), 7.02(2H, br s), 7.25-7.44(6H, m), 8.35(1H, d, J 4.0Hz) and 9.28(1H, t, J 6.0Hz); Retention time: 7.81min 131 I 17 IR ν_(max)(Nujol)/cm⁻¹ 4332, 4258, 3421, 3299, 3193, 3105, 2924, 2854, 1682, 1631, 1596, 1465, 1376, 747; NMR δ_(H)(400MHz, CDCl₃) 3.09(2H, m), 3.86(2H, br m), 4.80(2H, br m), 5.10(2H, s), 6.66(1H, dd, J 3.5, 1.7Hz), 7.18-7.25(4H, m), 7.74(1H, m), 7.85(1H, m) and 8.12(1H, s); Retention time: 2.25min (80:50) 132 I 81 IR ν_(max)(Nujol)/cm⁻¹ 4331, 3293, 3164, 2924, 2854, 1694, 1638, 1467, 746; NMR δ_(H)(400MHz, CDCl₃) 3.23(2H, m), 4.33(2H, m), 5.13(2H, s), 6.67(1H, dd, J 3.5, 1.7Hz), 7.10-7.31(4H, m), 7.74(1H, m), 7.74(1H, m), 7.86(1H, m) and 8.16(1H, s); M/Z 369(M+Na)⁺; Retention time: 2.80min (80:50) 133 A 11 mp >240° C. dec; IR ν_(max)(Nujol)/cm⁻¹ 3465, 3321, 2925, 1619, 1567, 1460, 1384, 1304, 1056, 832 and 740; NMR δ_(H)(400MHz, DMSO) 4.11(3H, s), 6.15(3H, m), 6.98(1H, t, J 2.0Hz), 7.60(1H, br s), 7.96(1H, s) and 12.43(1H, br s); Retention time: 1.67min 134 G 68 mp >230° C. dec; IR ν_(max)(Nujol)/cm⁻¹ 3465, 3364, 2924, 1722, 1609, 1549, 1462, 1062 and 732; NMR δ_(H)(400MHz, DMSO) 4.12(3H, s), 4.67(2H, d, J 6.0Hz), 6.20(1H, dd, J 4.0, 2.5Hz), 6.80(2H, br s), 7.08(1H, t, J 2.0Hz), 7.25-7.33(1H, m), 7.34-7.43(4H, m), 7.68(1H, dd, J 4.0, 2.0Hz), 8.41(1H, s) and 9.43(1H, t, J 6.0Hz); Retention time: 5.26min 137 Y 39 mp 300° C. (dec); IR ν_(max)(Nujol)/cm⁻¹ 3423, 3313, 2924, 1622, 1580, 1464, 1389, 1305, 1114, 888 and 633; NMR δ_(H)(400MHz, DMSO) 6.46(2H, br s), 8.15(1H, s), 9.11(1H, s), 9.27(1H, s) and 12.72(1H, br s); Retention time: 1.24min 139 G 76 mp 188° C.; IR ν_(max)(Nujol)/cm⁻¹ 3313, 3195, 2924, 1718, 1629, 1558, 1467, 1392, 1254, 890, 792 and 702; NMR δ_(H)(400MHz, DMSO) 4.65(2H, d, J 6.5Hz), 7.09(2H, br s), 7.25-7.32(1H, m), 7.34-7.44(4H, m), 8.59(1H, s), 9.11(1H, s), 9.27(1H, t, J 6.5Hz) and 9.35(1H, s); Retention time: 4.34min 140 Q 80 Mp 299.2-299.3° C.; IR ν_(max)(Nujol)/cm⁻¹ 3483, 3259, 3187, 2923, 2854, 1661, 1631, 1603, 1570, 1537, 1462, 1416 and 1378; NMR δ_(H)(400MHz, DMSO) 9.69(1H, br s), 8.11(1H, s), 7.95(1H, s), 7.73(1H, d, J 3.3Hz), 7.43(1H, d, J 7.6Hz), 7.23-7.07(3H, m), 6.75(1H, dd, J 3.3, 1.7Hz), 6.49(2H, br s), 5.04(2H, s) and 2.25(3H, s); Anal. Calcd for C₁₈H₁₆N₆O₂.0.8 H₂O: C, 59.59; H, 4.89; N, 20.17. Found: C, 59.43; H, 4.60; N, 20.27. 141 Q 60 Mp 278° C. (dec); IR ν_(max)(Nujol)/cm⁻¹ 3480, 3257, 3179, 2924, 2854, 1678, 1661, 1627, 1592, 1545, 1463 and 1415; NMR δ_(H)(400MHz, DMSO) 10.59(1H, br s), 8.10(1H, s), 7.95(1H, s), 7.76-7.73(2H, m), 7.45(1H, d, J 9.2Hz), 7.36(1H, t, J 8.0Hz), 7.13(1H, m), 6.75(1H, dd, J 3.6, 2.0Hz), 6.50(2H, s) and 5.01(2H, s); Anal. Calcd for C₁₇H₁₃ClN₆O₂.0.25 H₂O: C, 54.70; H, 3.65; N, 23.51. Found: C, 54.53; H, 3.50; N, 23.50. 142 Q 20 Mp 281.3-283.2° C.; IR ν_(max)(Nujol)/cm⁻¹ 3185, 2923, 2854, 1704, 1638, 1591, 1571, 1541, 1464, 1416, 1377 and 1297; NMR δ_(H)(400MHz, DMSO) 10.80(1H, br s), 8.45(2H, d, J 5.6Hz), 8.10(1H, s), 7.95(1H, s), 7.73(1H, d, J 3.2Hz), 7.54(2H, d, J 6.4Hz), 6.75(1H, dd, J 3.2, 1.6Hz), 6.51(2H, br s) and 5.05(2H, s). 143 Q 63 Mp 285.6-286.4° C.; IR ν_(max)(Nujol)/cm⁻¹ 3472, 3176, 2924, 2854, 1698, 1640, 1591, 1560, 1460, 1415, 1377 and 1297; NMR δ_(H)(400MHz, DMSO) 10.63(1H, br s), 8.74(1H, d, J 2.4Hz), 8.29(1H, d, J 3.6Hz), 8.11(1H, s), 8.00(1H, m), 7.95(1H, s), 7.74(1H, d, J 3.2Hz), 7.36(1H, dd, J 8.4, 4.8Hz), 6.75(1H, dd, J 3.2, 1.6Hz), 6.51(2H, br s) and 5.04(2H, s); Anal. Calcd for C₁₆H₁₃N₇O₂.2.2 H₂O: C, 51.25; H, 4.68; N, 26.15. Found: C, 51.33; H, 4.51; N, 26.18. 144 Q 51 Mp 277° C. (dec); IR ν_(max)(Nujol)/cm⁻¹ 3486, 3272, 3181, 2924, 2854, 1650, 1633, 1594, 1555, 1492, 1463, 1412 and 1377; NMR δ_(H)(400MHz, DMSO) 8.70(1H, br t, J 6.0Hz), 8.07(1H, s), 7.94(1H, s), 7.72(1H, d, J 3.2Hz), 7.42-7.30(4H, m), 6.74(1H, dd, J 3.2, 1.6Hz), 6.50(2H, br s), 4.84(2H, s) and 4.30(2H, d, J 5.6Hz). 145 Q 64 Mp 224.0-224.1° C.; IR ν_(max)(Nujol)/cm⁻¹ 3476, 3317, 3196, 3072, 2924, 2854, 1654, 1628, 1607, 1592, 1570, 1515, 1490, 1458, 1413, 1360, 1304 and 1292; NMR δ_(H)(400MHz, DMSO) 8.04(1H, s), 7.94(1H, d, J 1.0Hz), 7.73(1H, d, J 2.9Hz), 7.48-7.25(5H, m), 6.75(1H, dd, J 3.4, 1.8Hz), 6.48(2H, br s), 5.13(2H, s), 4.53(2H, s) and 3.07(3H, s). 146 S 16 NMR δ_(H)(400MHz, CDCl₃) 3.19(2H, t, J 7.0Hz), 4.38(2H, t, J 7.0Hz) 5.08(2H, br s), 6.63(1H, dd, J 1.5, 3.5Hz), 7.04(2H, dd, J 1.5, 4.5Hz), 7.49(1H, s), 7.72(1H, dd, J 1.0, 2.5Hz), 7.78(1H, dd, J 1.5, 3.5Hz) and 8.52(2H, dd, J 1.5, 4.5Hz); Retention time: 2.71min, (50:20). 147 S 9 NMR δ_(H)(400MHz, CDCl₃) 2.52(4H, t, J 4.7Hz), 2.76(2H, t, J 6.0Hz), 3.69(4H, t, J 4.7Hz), 4.10(2H, t, J 6.0Hz), 5.04(2H, br s), 6.64(1H, dd, J 1.5, 3.5Hz), 7.71(1H, dd, J 1.0, 1.5Hz), 7.79(1H, dd, J 1.0, 3.5Hz) and 7.94(1H, s); Retention time: 1.96min, (50:20). 148 S 17 NMR δ_(H)(400MHz, CDCl₃) 5.06(2H, br s), 5.31(2H, s), 6.63(1H, dd, J 2.0, 3.5Hz), 7.28(1H, m), 7.60(1H, m), 7.72(1H, dd, J 1.0, 2.5Hz), 7.77(1H, s), 7.80(1H, dd, J 1.0, 3.5Hz), 8.59(1H, dd, J 1.5, 5.0Hz) and 8.67(1H, d, J 2.5Hz); Retention time: 2.51min, (50:20). 150 A 10 mp 247-248° C.; NMR δ_(H)(400MHz, DMSO) 2.66(3H, s), 6.28(2H, br s), 7.03(1H, d, J 5.0Hz), 7.63(1H, d, J 5.0Hz), 8.03(1H, s) and 12.57(1H, br s); Retention time: 2.91min 151 AA 11 IR ν_(max)(Nujol)/cm⁻¹ 3317, 3194, 2923, 2854, 1732, 1456; NMR δ_(H)(400MHz, CDCl₃) 2.92(2H, t, J 6.4Hz), 3.67(3H, s), 4.40(2H, t, J 6.4Hz), 5.30(2H, br s), 6.62(1H, dd, J 1.6, 3.4Hz), 7.70(1H, dd, J 0.7, 1.6Hz), 7.79(1H, dd, J 0.7, 3.4Hz and 7.87(1H, s). 152 M 99 IR ν_(max)(Nujol)/cm⁻¹ 3500-2800 br, 2923, 2855, 1715, 1644, 1588, 1520, 1465, 1412 and 1378; NMR δ_(H)(400MHz, DMSO) 8.07(1H, s), 7.94(1H, m), 7.70(1H, m), 6.73(1H, dd, J 3.5, 1.5Hz), 6.55(2H, br s), 4.25(2H, t) and 2.85(2H, t, J 6.5Hz); M/Z 274(M+H)⁺. 153 AB 30 Mp. 342° C. dec.; IR ν_(max)(Nujol)/cm⁻¹ 2925, 2855, 1587, 1463, 1377, 846; NMR δ_(H)(400MHz, DMSO) 2.68(3H, s), 6.78(1H, m), 7.80(1H, m), 8.00(1H, m), 8.40(1H, m) and 13.32(1H, br). 154 G 46 Mp 152° C. (dec); IR ν_(max)(Nujol)/cm⁻¹ 3273, 3109, 2920, 2854, 1727, 1600, 1588, 1551, 1481, 1455, 1401 and 1374; NMR δ_(H)(400MHz, DMSO) 9.26(1H, t, J 5.9Hz), 8.92(1H, s), 8.09(1H, m), 7.85(1H, m), 7.30-7.50(5H, m), 6.84(1H, dd, J 3.5, 1.5Hz), 4.68(2H, d, J 5.9Hz) and 2.76(3H, s); Retention time 5.38min. (80:50) 155 H NMR δ_(H)(400MHz, CDCl₃) 8.25(1H, s), 8.09(1H, d, J 6.8Hz), 7.84(1H, d, J 3.6Hz), 6.66(1H, dd, J 3.6, 1.6Hz), 5.15(2H, br s), 4.07(1H, m) and 1.44(6H, d, J 6.8Hz). 156 AC 6 IR ν_(max) (Nujol)/cm⁻¹ 2923, 2854, 1588, 1564, 1486, 1462, 1376, 1352, 1309 and 1236; NMR δ_(H)(400MHz, CDCl₃) 7.96(1H, s), 7.88(1H, m), 7.75(1H, m), 7.20(4H, m), 6.50(1H, m), 5.35(2H, s) and 2.35(3H, s). 157 AC NMR δ_(H)(400MHz, DMSO) 5.38(2H, s), 6.56(2H, br s), 6.75(1H, dd, J 1.5, 3.5Hz), 7.10(1H, m), 7.16(1H, m), 7.25(1H, m), 7.37(1H, m), 7.72(1H, d, J 3.5Hz), 7.95(1H, dd, J 1.0, 2.0Hz) and 8.15(1H, s); Retention time: 1.58min, (80:50). 158 AC 60 mp 284.5-285.3° C.; IR ν_(max)(Nujol)/cm⁻¹ 3319, 3195, 3139, 3091, 1641, 1590, 1557, 1530, 1463, 1377 and 1349; NMR δ_(H)(400MHz, DMSO) 5.47(2H, s), 6.58(2H, s), 6.72-6.78(1H, m), 7.65(1H, dt, J 7.5, 1.0Hz), 7.69-7.76(2H, m), 7.95(1H, t, J 1.0Hz), 8.15-8.16(1H, m), 8.17(1H, s), 8.26(1H, s); Anal. Calcd for C₁₆H₁₂N₆O₃.0.35 H₂O: C, 56.09; H, 3.74; N, 24.53. Found: C, 56.10; H, 3.72; N, 24.40. 159 AC 46 mp 212.8-212.9° C.; NMR δ_(H)(400MHz, DMSO) 5.43(2H, s), 6.57(2H, s), 6.73-6.78(1H, m), 7.45(2H, d, J 8.0Hz), 7.70-7.75(3H, m), 7.95-7.97(1H, m), 8.24(1H, s); Anal. Calcd for C₁₇H₁₂N₅OF₃.0.1 H₂O: C, 56.54; H, 3.41; N, 19.39. Found: C, 56.65; H, 3.62; N, 19.01. 160 H 95 NMR δ_(H)(400MHz, DMSO) 6.76(1H, dd, J 2.0, 3.5Hz), 7.05(2H, br s), 7.67(1H, d, J 3.5Hz), 7.99(2H, m), 8.56(1H, s), 8.62(1H, dd, J 1.5, 8.0Hz), 8.72(1H, d, J 8.0Hz) and 8.89(1H, t, J 2.0Hz); Retention time: 4.15min, (80:50). 161 H 55 IR ν_(max)(Nujol)/cm⁻¹ 3493, 3405, 3309, 3192, 2924, 2854, 1624, 1586, 1565, 1467 and 1351; NMR δ_(H)(400MHz, DMSO) 6.77(1H, dd, J 2.0, 3.5Hz), 6.86(2H, br, s), 7.70(1H, d, J 3.5Hz), 7.72-7.76(2H, m), 7.90(1H, dd, J 2.0, 7.0Hz), 8.00(1H, d, J 1.5Hz), 8.39(1H, dd, J 2.5, 7.5Hz) and 8.62(1H, s); Retention time 4.54min, (80:50). 162 H 69 IR ν_(max)(Nujol)/cm⁻¹ 3503, 3324, 3202, 3115, 2924, 2854, 1634, 1587, 1569, 1467, 1392 and 1350; NMR δ_(H)(400MHz, DMSO) 6.76(1H, dd, J 2.0, 3.5Hz), 7.04(2H, br s), 7.67(1H, dd, J 0.5, 3.5Hz), 7.92(2H, d, J 8.5Hz), 7.98(1H, dd, J 1.0, 2.0Hz), 8.17(2H, d, J 9.0Hz) and 8.50(1H, s); Retention time 2.01min, (80:50). 163 H 36 IR ν_(max)(Nujol)/cm⁻¹ 3505, 3327, 3206, 2924, 2854, 1634, 1593, 1567, 1480, 1465, 1384 and 1348; NMR δ_(H)(400MHz, DMSO) 6.76(1H, dd, J 1.5, 3.5Hz), 7.04(2H, br s), 7.54(2H, t, J 9.0Hz), 7.67(1H, dd, J 0.5, 3.5Hz), 7.98(1H, dd, J 1.0, 2.0Hz), 8.34(1H, dd, J 5.0, 9.0Hz) and 8.50(1H, s); Retention time 3.89min, (80:50). 164 H 29 IR ν_(max)(Nujol)/cm⁻¹ 3484, 3301, 3184, 3107, 2924, 2854, 1661, 1633, 1588, 1465, 1376, 1356 and 1166; NMR δ_(H)(400MHz, DMSO) 3.78(3H, s), 6.78(1H, dd, J 2.0 3.5Hz), 7.05(2H, br s), 7.72(1H, m), 8.01(1H, m) and 8.31(1H, s); Retention time 3.22min, (80:50). 165 H 34 NMR δ_(H)(400MHz, DMSO) 0.84(3H, t, J 7.2Hz), 1.36(2H, sextet, J 7.2Hz), 1.65(2H, m), 3.93(2H, m), 6.78(1H, dd, J 2.0, 3.5Hz), 7.05(2H, br s), 7.73(1H, dd, J 1.0, 3.5Hz), 8.01(1H, dd, J 1.0, 1.5Hz) and 8.32(1H, s); Retention time 2.27(80:50). 166 H 55 NMR δ_(H)(400MHz, DMSO) 6.74(1H, dd, J 1.5, 3.5Hz), 6.76(2H, br s), 7.66(2H, m), 7.92(1H, t, J 8.0Hz), 7.95(1H, dd, J 1.0, 2.0Hz), 8.48(1H, dd, J 1.5, 8.0Hz), 8.55(1H, dd, J 1.5, 8.5Hz), 8.72(1H, dd, J 1.5, 7.5Hz), 8.75(1H, s) and 8.95(1H, dd, J 1.5, 4.5Hz); Retention time 3.29min, (80:50). 167 H 26 NMR δ_(H)(400MHz, DMSO) 2.38(3H, s), 2.87(3H, s), 6.77(1H, dd, J 1.5 3.5Hz), 6.97(2H, br s), 7.70(1H, dd, J 1.0, 3.5Hz), 8.00(1H, dd, J 1.0, 1.5Hz) and 8.57(1H, s); Retention time: 3.70min, (80:50). 168 H 58 NMR δ_(H)(400MHz, DMSO) 6.76(1H, dd, J 1.5, 3.5Hz), 7.43(1H, ddd, J 1.0, 5.0, 7.5Hz), 7.68(1H, dd, J 1.0, 3.5Hz), 7.93(1H, dt, J 1.5, 7.5Hz), 7.97(1H, d, J 4.5Hz), 7.99(1H, dd, J 1.0, 1.5Hz), 8.09(1H, dt, J 1.0, 8.0Hz), 8.24(1H, d, J 4.0Hz), 8.52(1H, s) and 8.59(1H, ddd, J 1.0, 5.0, 5.5Hz); Retention time 5.71min, (80:50). 169 Q Mp 287.1-288.2° C.; IR ν_(max)(Nujol)/cm⁻¹ 3200, 2920, 2854, 1666, 1651, 1591, 1568, 1538, 1503, 1453, 1416, 1378, 1282 and 1233; NMR δ_(H)(400MHz, DMSO) 9.60(1H, br s), 8.11(1H, s), 7.96(1H, s), 7.73(1H, d, J 3.2Hz), 7.25(1H, d, J 8.4Hz), 6.80(1H, d, J 2.8Hz), 6.76-6.71(2H, m), 6.52(2H, br s), 5.00(2H, s), 3.71(3H, s) and 2.20(3H, s). 170 Q NMR δ_(H)(400MHz, DMSO) 9.63(1H, br s), 8.11(1H, s), 7.95(1H, s), 7.73(1H, s), 7.28(1H, d, J 8.0Hz), 7.03(1H, s), 6.97(1H, m), 6.75(1H, s), 6.52(2H, br s), 5.02(2H, s), 2.24(3H, s) and 2.20(3H, s). 171 I 57 Mp 134.6° C.; NMR δ_(H)(400MHz, DMSO) 8.35(1H, s), 7.88(1H, m), 7.65(1H, m), 7.30-7.40(5H, m), 6.67(1H, dd, J 3.5, 1.5Hz), 4.75(2H, br m), 3.09(3H, br m) and 2.86(3H, s); Retention time 2.56min (80:50) 172 AC 28 mp 245.6-246.0° C.; IR ν_(max)(Nujol)/cm⁻¹ 3393, 3318, 3189, 3091, 1794, 1740, 1646, 1592, 1519, 1466, 1408, 1342 and 1310; NMR δ_(H)(400MHz, DMSO) 5.49(2H, s), 6.58(2H, s), 6.74-6.79(1H, m), 7.47-7.51(2H, m), 7.75(1H, dd, J 3.5Hz, 1.0Hz), 7.96-7.98(1H, m), 8.19-8.24(2H, m) and 8.26(1H, s). 173 AH 57 Mp. 196.5° C. dec.; IR ν_(max)(Nujol)/cm⁻¹ 2923, 2852, 2243, 1596, 1463, 1378, 1144; NMR δ_(H)(400MHz, CDCl₃) 2.35(3H, s), 5.42(2H, s), 6.69(1H, dd J 1.8, 3.5Hz), 7.19(2H, m), 7.25(2H, m), 7.82(1H, m), 7.90(1H, m) and 8.19(1H, br s). 174 X 43 Mp 160° C. (dec); IR ν_(max)(Nujol)/cm⁻¹ 3347, 2924, 2854, 1771, 1718, 1607, 1593, 1562, 1460, 1403 and 1378; NMR δ_(H)(400MHz, DMSO) 8.07(1H, s), 7.93(1H, d, J 2.0Hz), 7.80(4H, s), 7.67(1H, d, J 4.0Hz), 6.72(1H, dd, J 3.5, 2.0Hz), 6.19(2H, br s), 4.37-4.30(2H, m), 4.04-3.96(2H, m) and 3.30(3H, s). 175 Q NMR δ_(H)(400MHz, DMSO) 10.55(1H, br s), 8.10(1H, s), 7.96(1H, s), 7.74(1H, s), 7.60(2H, m), 7.39(2H, m), 6.76(1H, s), 6.53(2H, br s) and 5.01(2H, s). 176 Q NMR δ_(H)(400MHz, DMSO) 10.72(1H, br s), 8.10(1H, s), 7.96(1H, s), 7.94(1H, s), 7.74(1H, s), 7.59(1H, d, J 8.8Hz), 7.49(1H, d, J 8.4Hz), 6.76(1H, s), 6.54(2H, s) and 5.02(2H, s). 177 AC 50 mp 302.5-304.8° C.; IR ν_(max)(Nujol)/cm⁻¹ 3356, 3314, 3198, 2232, 1636, 1618, 1591, 1557, 1515 and 1463; NMR δ_(H)(400MHz, DMSO) 5.38(2H, s), 6.58(2H, s), 6.73-6.78(1H, m), 7.54-7.61(2H, m), 7.73(1H, d, J 3.5Hz), 7.76-7.80(2H, m), 7.94-7.96(1H, m), 8.23(1H, s); Anal. Calcd for C₁₇H₁₂N₆O.0.4 H₂O: C, 63.11; H, 3.99; N, 25.98. Found: C, 63.18; H, 3.92; N, 26.02. 178 AC 32 IR ν_(max)(Nujol)/cm⁻¹ 1644, 1584, 1463, 1408 and 1377; NMR δ_(H)(400MHz, DMSO) 5.44(3H, s), 6.92-6.95(1H, m), 7.03-7.06(1H, m), 7.32(1H, dt, J 7.5Hz, 1.5Hz), 7.39(1H, dt, J 7.5Hz, 1.5Hz), 7.55(1H, dd, J 8.0Hz, 1.0Hz), 7.98(1H, d, J 3.5Hz), 8.23(1H, s) and 8.51(1H, s). 179 H 38 NMR δ_(H)(400MHz, DMSO) 4.67(2H, d, J 5.5Hz), 6.76(1H, dd, J 1.5, 3.5Hz), 7.05(2H, br s), 7.23(1H, d, J 4.0Hz), 7.55(2H, d, J 8.5Hz), 7.67(1H, d, J 3.5Hz), 7.87(1H, d, J 8.5Hz), 7.99(1H, dd, J 1.0 1.5Hz), 8.10(1H, d, J 4.5Hz), 8.48(1H, s) and 9.34(1H, t, J 6.0Hz); Retention time 5.38min, (80:50). 180 H 34 NMR δ_(H)(400MHz, DMSO) 6.75(1H, dd, J 2.0, 3.5Hz), 6.95(2H, br s), 7.66(1H, dd, J 1.0, 3.5Hz), 7.89(1H, dd, J 7.0, 9.0Hz), 7.97(1H, dd, J 1.0, 1.5Hz), 8.55(1H, dd, J 1.0, 9.0Hz) and 8.64(2H, t, J 3.5Hz); Retention time 3.82min, (80:50). 181 H IR ν_(max)(Nujol)/cm⁻¹ 3480, 3317, 3203, 2923, 2854, 1723, 1626, 1588, 1566, 1466, 1378, 1350 and 1268; NMR δ_(H)(400MHz, DMSO) 3.83(3H, s), 6.77(1H, dd, J 1.5, 3.5Hz), 6.89(2H, br s), 7.70(1H, dd, J 1.5, 3.5Hz), 7.80(1H, d, J 5.5Hz), 7.99(1H, dd, J 0.5, 1.5Hz), 8.12(1H, d, J 5.0Hz) and 8.49(1H, s); Retention time 2.71min, (80:50). 182 H 61 NMR δ_(H)(400MHz, DMSO) 4.39(2H, br s), 6.77(1H, dd, J 1.5, 3.5Hz), 7.20(1H, d, J 2.0Hz), 7.69(1H, dd, J 1.0, 3.5Hz), 7.87(1H, d, J 4.0Hz), 8.01(1H, dd, J 1.0, 1.5Hz), 8.29(1H, d, J 4.0Hz), 8.54(1H, s) and 8.76(1H, d, J 2.0Hz); Retention time 4.72min, (80:50). 183 H IR ν_(max)(Nujol)/cm⁻¹ 3424, 3323, 3208, 2924, 2854, 1634, 1586, 1565, 1502, 1464, 1378 and 1352; NMR δ_(H)(400MHz, DMSO) 2.56(3H, s), 3.75(3H, s), 6.76(1H, dd, J 1.5, 3.5Hz), 6.88(2H, br s), 7.69(1H, dd, J 1.0, 3.5Hz), 7.99(1H, dd, J 0.5, 2.0Hz) and 8.49(1H, s); Retention time 2.98min, (80:50). 184 H 47 NMR δ_(H)(400MHz, DMSO) 2.62(3H, s), 6.76(1H, dd, J 1.5, 0.5Hz), 7.06(2H, br s), 7.68(1H, dd, J 1.0, 3.5Hz), 7.99(1H, dd, J 1.0, 1.5Hz), 8.18(2H, d, J 8.5Hz), 8.38(2H, d, J 8.5Hz) and 8.54(1H, s); Retention time 3.27min, (80:50). 185 H 59 IR ν_(max)(Nujol)/cm⁻¹ 3493, 3334, 2924, 2854, 1627, 1591, 1565, 1469, 1378, 1346, 1156 and 1145; NMR δ_(H)(400MHz, DMSO) 6.76(1H, dd, J 1.5, 3.5Hz), 6.98(2H, br s), 7.46-7.53(3H, m), 7.70(1H, dd, J 1.0, 3.5Hz), 7.73(1H, d, J 15.5Hz), 7.81(2H, dd, J 1.5, 8.5Hz), 7.99(1H, dd, J 1.0, 2.0Hz), 8.06(1H, J 15.5Hz) and 8.39(1H, s); Retention time 4.77min, (80:50). 186 H 18 NMR δ_(H)(400MHz, DMSO) 1.25(3H, t, J 7.5Hz), 3.92(2H, q, J 7.5Hz), 6.78(1H, dd, J 1.5, 3.5Hz), 7.05(2H, br s), 7.73(1H, d, J 3.5Hz), 8.01(1H, dd, J 1.0, 2.0Hz) and 8.32(1H, s); Retention time 1.0, (80:50). 187 S 34 NMR δ_(H)(400MHz, CDCl₃) 5.10(2H, br s), 5.42(2H, s), 6.64(1H, dd, J 1.5, 3.5Hz), 7.20(1H, d, J 8.0Hz), 7.23(1H, m), 7.65(1H, dt, J 2.0, 7.5Hz), 7.71(1H, m), 7.82(1H, d, J 4.0Hz), 7.96(1H, s) and 8.58(1H, m); Retention time 2.66min, (50:20). 188 S 30 IR ν_(max)(Nujol)/cm⁻¹ 3315, 3190, 2924, 1586, 1567, 1513, 1462, 1408 and 1377; NMR δ_(H)(400MHz, CDCl₃) 1.75(2H, br s), 5.11(2H, br s), 6.65(1H, dd, J 1.5, 2.5Hz), 7.12(2H, dd, J 1.0, 4.5Hz), 7.73(1H, dd, J 1.0, 2.0Hz), 7.78(1H, s), 7.83(1H, dd, J 1.0, 3.5Hz), and 8.60(2H, dd, J 1.5, 4.5Hz); Retention time 2.27min, (50:20). 189 S 43 IR ν_(max)(Nujol)/cm⁻¹ 3501, 3303, 3176, 3150, 2933, 2855, 1640, 1604, 1587, 1568, 1515, 1466, 1411 and 1378; NMR δ_(H)(400MHz, CDCl₃) 2.26(2H, quintet, J 7.5Hz), 2.69(2H, t, J 7.5Hz), 4.16(2H, t, J 7.0Hz), 5.12(2H, br s), 6.64(1H, dd, J 1.5, 3.5Hz), 7.24(1H, ddd, J 1.0, 5.0, 8.0Hz), 7.51(1H, dt, J 2.0, 8.0, 8.1Hz), 7.74(1H, dd, J 1.0, 2.0Hz), 7.76(1H, s), 7.80(1H, dd, J 1.0, 3.5Hz), 8.48(1H, dd, J 1.5, 5.0Hz) and 8.51(1H, d, J 2.0Hz); Retention time 4.15min, (50:20). 190 S 31 NMR δ_(H)(400MHz, CDCl₃) 2.26(2h, quintet, J 7.5Hz), 2.68(2H, t, J 7.5Hz), 4.16(2H, t, J 7.0Hz), 5.08(2H, br s), 6.64(1H, dd, J 1.5, 3.5Hz), 7.12(2H, dd, J 1.5, 4.5Hz), 7.72(1H, dd, J 1.0, 1.5Hz), 7.75(1H, s), 7.80(1H, dd, J 1.0, 3.5Hz) and 8.52(2H, dd, J 1.5, 4.5Hz); Retention time 3.95min, (50:20). 191 G 39 NMR δ_(H)(400MHz, DMSO) 1.58(3H, d, J 7.0Hz), 5.09(1H, m), 6.78(1H, dd, J 1.5, 3.5Hz), 7.13(2H, br s), 7.42(2H, d, J 8.5Hz), 7.57(2H, d, J 8.5Hz), 7.75(1H, dd, J 1.0, 3.5Hz), 8.01(1H, dd, J 1.0, 2.0Hz), 8.44(1H, s) and 1.33(1H, d, J 7.5Hz); Retention time 6.28min, (80:50). 192 AD 22 IR ν_(max)(Nujol)/cm⁻¹ 3404, 3347, 3137, 3089, 1661, 1647, 1628, 1535, 1517, 1466, 1420 and 1377; NMR δ_(H)(400MHz, DMSO) 3.51-4.43(6H, s), 5.37(2H, s), 6.84-6.86(1H, m), 7.03(1H, s), 7.16(2H, t, J 10.0Hz), 7.40(1H, t, J 7.5Hz), 7.86(1H, d, J 3.0Hz), 8.10(1H, s) and 8.42(1H, s). 193 AC 36 mp 216.5-216.6° C.; IR ν_(max)(Nujol)/cm⁻¹ 3483, 3298, 3186, 3096, 1721, 1624, 1595, 1514, 1489, 1456, 1409, 1379, 1287 and 1202; NMR δ_(H)(400MHz, DMSO) 3.83(3H, s), 5.40(2H, s), 6.74-6.76(1H, m), 7.49-7.58(2H, m), 7.72-7.74(1H, m), 7.85-7.91(2H, m), 7.96(1H, t, J 1.0Hz) and 8.25(1H, s); Anal. Calcd for C₁₈H₁₅N₅O₃: C, 61.89; H, 4.33; N, 20.55. Found: C, 61.77; H, 4.38; N, 19.96. 194 AC 45 IR ν_(max)(Nujol)/cm⁻¹ 3309, 3089, 2231, 1645, 1517, 1466, 1410, 1378 and 1304; NMR δ_(H)(400MHz, DMSO) 5.45(2H, s), 6.85-6.90(1H, m), 7.45(2H, d, J 8.5Hz), 7.84(2H, d, J 8.5Hz), 7.88(1H, d, J 3.5Hz), 8.15(1H, s) and 8.48(1H, s). 195 Y 21 mp >190° C. (dec); IR ν_(max)(Nujol)/cm⁻¹ 3492, 3302, 3085, 2918, 1629, 1580, 1456, 1031, 817 and 627; NMR δ_(H)(400MHz, DMSO) 2.40(3H, s), 6.42-6.31(3H, m), 7.66(1H, d, J 3.0Hz), 8.02(1H, s) and 12.54(1H, br s); Retention time (80:50) 0.65min 196 H 27 NMR δ_(H)(400MHz, DMSO) 0.82(3H, t, J 7.5Hz), 1.15-1.30(6H, m), 1.66(2H, quintet, J 7.5Hz), 3.92(2H, t, J 7.5Hz), 6.78(1H, dd, J 1.5, 3.5Hz), 7.05(2H, br s), 7.72(1H, d, J 3.5Hz), 8.01(1H, dd, J 1.0, 1.5Hz) and 8.32(1H, s); Retention time 7.72(80:50). 197 AC 74 mp 290.6-290.7° C.; NMR δ_(H)(400MHz, DMSO) 5.69(2H, s), 6.58(2H, s), 6.75-6.79(1H, m), 6.87(1H, d, J 7.5Hz), 7.60(1H, t, J 7.5Hz), 7.68(1H, d, J 3.5Hz), 7.97(1H, s) and 8.14-8.20(2H, m). 198 AC 17 mp 19.7-201.5° C.; NMR δ_(H)(400MHz, DMSO) 3.72(3H, s), 5.28(2H, s), 6.56(2H, s), 6.73-6.76(1H, m), 6.79-6.91(3H, m), 7.25(1H, t, J 7.5Hz), 7.72(1H, dd, J 3.5Hz, 1.0Hz), 7.94-7.96(1H, m) and 8.20(1H, s). 199 M 77 mp 294.0-294.3° C.; NMR δ_(H)(400MHz, DMSO) 5.40(2H, s), 5.75(1H, s), 6.57(2H, s), 6.74-6.77(1H, m), 7.45-7.56(2H, m), 7.74(1H, dd, J 3.5, 1.0Hz), 7.80-7.83(1H, m), 7.86(1H, dt, J 7.5, 1.5Hz), 7.95-7.97(1H, m), 8.25(1H, s) and 12.83-13.12(1H, s). 201 G 62 Mp. 350° C. dec.; NMR δ_(H)(400MHz, CDCl₃) 4.62(2H, m), 6.45(2H, m), 6.80(1H, m), 7.05(1H, br s), 7.63(1H, m), 7.77(1H, m), 8.03(1H, m), 8.50(1H, s) and 9.20(1H, m). 202 G 20 Mp 296.3° C.; IR ν_(max)(Nujol)/cm⁻¹ 3291, 3167, 3119, 2927, 1715, 1633, 1596, 1567, 1401 and 1376; NMR δ_(H)(400MHz, DMSO) 9.32(1H, t, J 6.0Hz), 8.46(1H, s), 8.05(1H, m), 7.75(1H, m), 7.45(1H, m), 7.15(1H, m), 7.00(3H, m), 6.78(1H, m) and 4.79(2H, d, J 6.0Hz); Retention time 3.52min (80:50) 203 AC 20 mp 218.2-218.5° C.; IR ν_(max)(Nujol)/cm⁻¹ 3335, 3201, 1654, 1586, 1520, 1470 and 1412; NMR δ_(H)(400MHz, DMSO) 5.35(2H, s), 6.57(2H, s), 6.74-6.77(1H, m), 7.07-7.17(3H, m), 7.36-7.44(1H, m), 7.73(1H, d, J 3.5Hz), 7.96(1H, s) and 8.22(1H, s). 204 G 50 Mp 160° C. (dec); IR ν_(max)(Nujol)/cm⁻¹ 3540, 3300, 3188, 3123, 2920, 2854, 1708, 1628, 1603, 1584, 1561, 1461, 1395 and 1377; NMR δ_(H)(400MHz, DMSO) 9.33(1H, br t, J 6.5Hz), 8.47(1H, s), 7.70(1H, d, J 3.5Hz), 7.44-7.33(4H, m), 7.32-7.25(1H, m), 7.00(2H, br s), 6.42(1H, dd, J 3.5, 1.0Hz), 4.63(2H, d, J 6.5Hz) and 2.42(3H, s). 205 AF 43 IR ν_(max)(Nujol)/cm⁻¹ 3516, 3294, 3170, 3144, 3075, 1655, 1629, 1589, 1540, 1464, 1410 and 1368; NMR δ_(H)(400MHz, DMSO) 1.98(3H, s), 5.30(2H, s), 6.55(2H, s), 6.74-6.77(1H, m), 6.92(1H, d, J 8.5Hz), 7.23-7.31(2H, m), 7.54(1H, d, J 8.0Hz), 7.72-7.75(1H, m), 7.95-7.96(1H, m), 8.18(1H, s) and 9.88(1H, s). 206 AC 19 mp 201.9-203.0° C.; NMR δ_(H)(400MHz, DMSO) 3.18(3H, s), 5.45(2H, s), 6.57(2H, s), 6.47-6.77(1H, m), 7.48(2H, d, J 8.5Hz), 7.74(1H, d, J 3.5Hz), 7.90(2H, d, J 8.5Hz), 7.95-7.97(1H, m) and 8.25(1H, s). 207 AD 34 IR ν_(max)(Nujol)/cm⁻¹ 3314, 1644, 1464, 1378, 1311, 1256 and 1117; NMR δ_(H)(400MHz, DMSO) 5.31(2H, s), 6.84-6.89(1H, m), 6.91-7.01(1H, m), 7.14(2H, t, J 7.5Hz), 7.24(1H, t, J 7.0Hz), 7.87(1H, d, J 3.5Hz), 8.14(1H, s), 8.47(1H, s). 208 AC 34 Mp 210-220° C. (dec); NMR δ_(H)(400MHz, DMSO) 7.77(1H, d, J 3.0Hz), 7.69(1H, s), 7.19-7.12(4H, m), 6.26-6.22(1H, m), 5.22(2H, s), 5.04(2H, br s), 2.49(3H, s) and 2.33(2H, s). 209 Y 58 Mp 300° C. (dec); NMR δ_(H)(400MHz, DMSO) 8.24(1H, s), 8.02(1H, s), 7.82(1H, s), 6.31(2H, br s) and 4.11(3H, s). 210 AF 16 mp 254.7-255.3° C.; NMR δ_(H)(400MHz, DMSO) 3.12(3H, s), 5.42(2H, s), 6.53(2H, s), 6.74-6.77(1H, m), 6.96(1H, d, J 7.0Hz), 7.21(1H, dt, J 7.5Hz, 1.0Hz), 7.34(1H, dt, J 7.0Hz, 1.5Hz), 7.39-7.43(1H, m), 7.74(1H, dd, J 3.5Hz, 1.0Hz), 7.96-7.97(1H, m), 8.17(1H, s). 211 AC 53 IR ν_(max)(Nujol)/cm⁻¹ 3325, 3194, 1650, 1589, 1519, 1467, 1411, 1377, 1305 and 1016; NMR δ_(H)(400MHz, DMSO) 5.37(2H, s), 6.51(2H, s), 6.72-6.75(1H, m), 7.15(2H, t, J 8.0Hz), 7.43-7.52(1H, m), 7.69(1H, dd, J 3.5Hz, 1.0Hz), 7.93-7.95(1H, m) and 8.05(1H, s). 212 S 43 NMR δ_(H)(400MHz, CDCl₃) 2.55(3H, s), 5.08(2H, br s), 5.37(2H, s), 6.63(1H, dd, J 1.5, 3.5Hz), 6.93(1H, d, J 7.8Hz), 7.07(1H, d, J 7.8Hz), 7.52(1H, t, J 7.5Hz), 7.71(1H, dd, J 1.0, 1.5Hz), 7.81(1H, dd, J 1.0, 3.5Hz) and 7.98(1H, s); Retention time 4.68min, (50:20). 213 S 11 NMR δ_(H)(400MHz, CDCl₃) 5.05(2H, br s), 5.14(2H, s), 6.38(1H, dd, J 1.0, 2.0Hz), 6.63(1H, dd, J 2.0, 3.0Hz), 7.41(1H, dd, J 1.5, 2.0Hz), 7.48(1H, dd, J 1.0, 2.0Hz), 7.71(1H, dd, J 1.0, 2.0Hz), 7.76(1H, s) and 7.79(1H, dd, J 1.0, 3.5Hz); Retention time 0.88min, (80:50). 214 H 17 NMR δ_(H)(400MHz, DMSO) 5.27(2H, s), 6.78(1H, dd, J 1.5, 3.5Hz), 7.12-7.18(3H, m), 7.33-7.38(2H, m), 7.68(1H, dd, J 1.0, 3.5Hz), 7.96(1H, s) and 8.04(1H, dd, J 1.0, 1.5Hz); Retention time 2.16min, (80:50). 215 AC 56 mp 219.5-219.7° C.; NMR δ_(H)(400MHz, DMSO) 3.86(3H, s), 5.42(2H, s), 6.57(2H, s), 6.74-6.77(1H, m), 7.36(2H, d, J 8.0Hz), 7.74(1H, d, J 3.0Hz), 7.91-7.98(3H, m) and 8.23(1H, s). 216 M 98 mp 301.1-302.1° C.; NMR δ_(H)(400MHz, DMSO) 5.42(2H, s) 6.80-6.84(1H, m), 7.36(2H, d, J 8.5Hz), 7.82(1H, d, J 3.0Hz), 7.93(2H, d, J 8.0Hz), 8.06(1H, s) and 8.38(1H, s). 217 AF 95 mp 171.2-171.3° C.; NMR δ_(H)(400MHz, DMSO) 5.42(2H, s), 6.80-6.84(1H, m), 7.36(2H, d, J 8.5Hz), 7.82(1H, d, J 3.0Hz), 7.89-7.94(2H, m), 8.06(1H, s) and 8.38(1H, s). 218 Q 52 mp 276.4-276.9° C.; NMR δ_(H)(400MHz, DMSO) 4.31(2H, d, J 5.5Hz), 4.81(2H, s), 6.29(1H, d, J 3.5Hz), 6.41(1H, m), 6.52(2H, s), 6.74-6.76(1H, m), 7.59-7.61(1H, m), 7.73(1H, d, J 3.0Hz), 7.95(1H, s), 8.06(1H, s) and 8.72(1H, t, J 5.5Hz). 219 AC 45 mp 205.3-205.4° C.; IR ν_(max)(Nujol)/cm⁻¹ 3571, 3384, 3328, 3215, 3081, 1645, 1394, 1523, 1480, 1466, 1409, 1364 and 1312; NMR δ_(H)(400MHz, DMSO) 3.69(6H, s), 5.22(2H, s), 6.41-6.46(2H, m), 6.56(2H, s), 6.73-6.76(1H, m), 7.72(1H, d, J 2.5Hz), 7.95(1H, d, J 1.0Hz) and 8.19(1H, s). 220 AF 10 NMR δ_(H)(400MHz, DMSO) 2.12(3H, s), 5.27(2H, s), 6.55(2H, s), 6.74-6.77(1H, m), 6.90(1H, d, J 7.0Hz), 7.13(1H, t, J 7.5Hz), 7.28(1H, dt, J 7.5Hz, 1.0Hz), 7.36-7.41(1H, m), 7.73(1H, d, J 3.5Hz), 7.95-7.97(1H, m), 8.10(1H, s) and 9.69(1H, s); Retention time 0.87min (80:20) 221 AG 48 IR ν_(max)(Nujol)/cm⁻¹ 4328, 1643, 1463, 1410, 1378 and 1284; NMR δ_(H)(400MHz, DMSO) 5.27(2H, s), 6.66(1H, t, J 1.5Hz), 6.68-6.74(2H, m), 6.90-6.96(1H, m), 7.15(1H, t, J 7.5Hz), 7.97(1H, d, J 3.5Hz), 8.23(1H, s) and 8.59(1H, s). 222 S 4 NMR δ_(H)(400MHz, CD, OD) 3.83(2H, t, J 5.6Hz), 4.43(2H, t, J 5.6Hz), 6.69(1H, dd, J 1.5, 3.5Hz), 7.63(2H, dd, J 1.5, 4.5Hz), 7.66(1H dd, J 1.0, 3.5Hz), 7.82(1H, dd, J 1.0, 2.0Hz), 8.06(1H, s) and 8.63(2H, dd, J 2.0, 4.5Hz). 223 S 9 IR ν_(max)(Nujol)/cm⁻¹ 3336, 3204, 3090, 2923, 2854, 1651, 1588, 1567, 1519, 1468, 1408, 1376 and 1302; NMR δ_(H)(400MHz, CDCl₃) 5.07(2H, br s), 5.29(2H, s), 6.63(1H, dd, J 1.5, 3.5Hz), 7.04(1H, dd, J 1.5, 5.0Hz), 7.22(1H, dd, J 1.0, 3.0Hz), 7.33(1H, dd, J 3.0, 5.0Hz), 7.71(1H, dd, J 1.0, 1.5Hz), 7.75(1H, s) and 7.80(1H, dd, J 1.0, 3.5Hz); Retention time 1.47min, (80:50). 224 S 15 NMR δ_(H)(400MHz, CDCl₃) 5.01(2H, br s), 5.24(2H, s), 5.33(2H, s), 6.62(1H, dd, J 2.0, 3.5Hz), 6.85(2H, dd, J 1.5, 8.0Hz), 6.93(1H, d, J 1.5Hz), 7.10(1H, d, J 1.5Hz), 7.12-7.21(3H, m), 7.69(1H, dd, J 1.0, 1.5Hz), 7.73(1H, dd, J 1.0, 3.5Hz) and 7.82(1H, s); Retention time 1.07min, (80:50). 225 AD 86 IR ν_(max)(Nujol)/cm⁻¹ 4330, 4259, 1642, 1579, 1513, 1464 and 1378; NMR δ_(H)(400MHz, DMSO) 5.34(2H, s), 6.84-6.87(1H, m), 7.25(2H, d, J 8.5Hz), 7.35(2H, d, J 8.5Hz), 7.88(1H, d, J 3.5Hz), 8.12(1H, s) and 8.45(1H, s). 226 P 92 mp 243.2-243.8° C.; IR ν_(max)(Nujol)/cm⁻¹ 3481, 3266, 3190, 1639, 1626, 1544, 1514, 1463, 1409 and 1378; NMR δ_(H)(400MHz, DMSO) 4.47(2H, d, J 6.0Hz), 5.37(2H, s), 6.54(2H, s), 6.75(1H, s), 7.19-7.25(1H, m), 7.26-7.33(4H, m), 7.37-7.49(2H, m), 7.73(1H, d, J 2.5Hz), 7.79-7.83(2H, m), 7.95(1H, s), 8.22(1H, s) and 8.99-9.05(1H, m). 227 P 47 mp 170.0-171.9° C.; IR ν_(max)(Nujol)/cm⁻¹ 3474, 3286, 3179, 1634, 1591, 1548, 1462, 1408, 1377 and 1308; NMR δ_(H)(400MHz, DMSO) 4.46(2H, d, J 6.0Hz), 5.38(2H, s), 6.56(2H, s), 6.73-6.77(1H, m), 7.19-7.26(1H, m), 7.28-7.36(5H, m), 7.73(1H, d, J 3.0Hz), 7.86(2H, d, J 8.5Hz), 7.96(1H, s), 8.23(1H, s) and 8.96(1H, t, J 6.0Hz); Anal. Calcd for C₂₄H₂₀N₆O₂.1.0 H₂O: C, 65.15; H, 5.01; N, 18.99. Found: C, 65.51; H, 4.66; N, 18.63. 228 H 54 IR ν_(max)(Nujol)/cm⁻¹ 3504, 3299, 3184, 3138, 1630, 1596, 1468, 1376 and 1353; NMR δ_(H)(400MHz, DMSO) 2.39(3H, s), 6.76(1H, s), 7.01(2H, s), 7.50(2H, d, J 7.0Hz), 7.67(1H, s), 7.98(1H, s), 8.13(2H, d, J 7.0Hz), 8.49(1H, s); Anal. calcd for C₁₆H₁₃N₅O₃S.0.8 H₂O: C, 51.97; H 3.98; N, 18.94. Found: C, 52.21; H, 3.79; N, 18.60. M/Z 355(M+H)⁺. 229 AC 40 mp 282.4-282.6° C.; NMR δ_(H)(400MHz, DMSO) 2.19(3H, s), 2.49(3H, s), 5.08(2H, s), 6.53(2H, s), 6.73-6.75(1H, m), 6.70(1H, d, J 2.5Hz), 7.94(1H, s) and 8.16(1H, s). 230 P 3 IR ν_(max)(Nujol)/cm⁻¹ 3390, 3325, 3215, 1640, 1586, 1518, 1467, 1410 and 1379; NMR δ_(H)(400MHz, DMSO) 2.85(3H, s), 2.95(3H, s), 5.35(2H, s), 6.57(2H, s), 6.73-6.76(1H, m), 7.29-7.35(3H, m), 7.41(1H, t, J 7.0Hz), 7.73(1H, d, J 3.5Hz), 7.94-7.97(1H, m) and 8.23(1H, s). 231 Q 45 mp 278.5-280.4° C.; IR ν_(max)(Nujol)/cm⁻¹ 3458, 3273, 3185, 1679, 1604, 1551, 1495, 1466 and 1378; NMR δ_(H)(400MHz, DMSO) 3.71(3H, s), 5.00(2H, s), 6.53(2H, s), 6.65(1H, dd, J 8.0Hz, 2.0Hz), 6.74-6.77(1H, m), 7.11(1H, d, J 8.0Hz), 7.23(1H, t, J 8.5Hz), 7.28(1H, t, J 2.0Hz), 7.74(1H, d, J 4.0Hz), 7.95-7.96(1H, m), 8.10(1H, s) and 10.41(1H, s); Anal. calcd for C₁₈H₁₆N₆O₃.0.7 H₂O: C, 57.35; H, 4.65; N, 22.29. Found: C, 57.27; H, 4.30; N, 22.29. 232 AF 10 IR ν_(max)(Nujol)/cm⁻¹ 3466, 3331, 3210, 1705, 1634, 1591, 1515, 1465, 1408, 1378, 1331, 1225 and 1152; NMR δ_(H)(400MHz, DMSO) 2.95(3H, s), 5.26(2H, s), 6.55(2H, s), 6.73-6.76(1H, m), 7.17(2H, d, J 8.5Hz), 7.27(2H, d, J 8.5Hz), 7.72(1H, d, J 3.0Hz), 7.95(1H, d, J 1.0Hz), 8.18(1H, s) and 9.73(1H, s). 233 P 45 mp 223.1-226.9° C.; NMR δ_(H)(400MHz, DMSO) 2.87(3H, s), 2.94(3H, s), 5.36(2H, s), 6.57(2H, s), 6.73-6.77(1H, m), 7.30(2H, d, J 8.5Hz), 7.37(2H, d, J 3.5Hz), 7.73(1H, d, J 3.5Hz), 7.94-7.97(1H, m) and 8.20-8.24(1H, m); Anal. calcd for C₁₉H₁₈N₆O₂.1.2 H₂O: C, 59.43; H, 5.35; N, 21.89. Found: C, 59.70; H, 5.16; N, 21.50. 234 AF 8 NMR δ_(H)(400MHz, DMSO) 0.83(4H, d, J 6.0Hz), 5.28(2H, s), 6.54(2H, s), 6.74-6.77(1H, m), 6.85(1H, d, J 7.5Hz), 7.12(1H, t, J 7.5Hz), 7.27(1H, t, J 7.5Hz), 7.42(1H, d, J 3.5Hz), 7.74(1H, d, J 3.5Hz), 7.94-7.98(1H, m), 8.10(1H, s) and 9.93(1H, s); Anal. calcd for C₂₀H₁₈N₆O₂.0.8 H₂O: C, 61.78; H, 5.08; N, 21.61. Found: C, 61.92; H, 4.81; N, 21.60. 235 AF 48 mp 253.1-257.1° C.; NMR δ_(H)(400MHz, DMSO) 3.68(3H, s), 5.36(2H, s), 6.59(2H, s), 6.72-6.80(1H, m), 6.97(1H, d, J 7.5Hz), 7.08-7.15(1H, m), 7.19-7.23(2H, m), 7.74(1H, d, J 3.5Hz), 7.77(1H, s), 7.84(1H, s), 7.97(1H, s), 8.08(1H, s) and 10.42(1H, s). 236 Q 54 mp 279.9-281.0° C.; NMR δ_(H)(400MHz, DMSO) 3.83(3H, s), 4.30(2H, d, J 4.5Hz), 4.82(2H, s), 6.23(2H, s), 6.72(1H, s), 6.88-7.00(2H, m), 7.24(1H, s), 7.70(1H, s), 7.89(1H, s), 8.03(1H, s) and 8.32(1H, s). 237 Q 60 mp 291.9-292.1° C.; NMR δ_(H)(400MHz, DMSO) 4.35(2H, s), 4.83(2H, s), 6.52(2H, s), 6.74(1H, s), 7.13-7.23(2H, m), 7.27-7.43(2H, m), 7.72(1H, s), 7.95(1H, s), 8.06(1H, s) and 8.71(1H, s). 238 AF 52 mp 265.6-266.0° C.; NMR δ_(H)(400MHz, DMSO) 5.27(2H, s), 6.56(2H, s), 6.76(1H, s), 6.94(2H, t, J 6.5Hz), 7.13-7.28(3H, m); 7.51-7.55(1H, m), 7.72-7.76(1H, m), 7.95-8.00(2H, m), 8.03(1H, s) and 10.39(1H, s); Anal. calcd for C₂₀H₁₆N₆O₃S₂.1.0 H₂O: C, 51.05; H, 3.86; N, 17.86. Found: C, 50.72; H, 3.48; N, 17.98. 239 AF 50 mp 251.4-253.1° C.; NMR δ_(H)(400MHz, DMSO) 2.13(3H, s), 2.31(3H, s), 5.37(2H, s), 6.52(2H, s), 6.74-6.77(1H, m), 6.90-6.94(1H, m), 6.99-7.03(1H, m), 7.25-7.32(2H, m), 7.74(1H, d, J 3.5Hz), 7.97(1H, s), 8.08(1H, s) and 10.28(1H, s). 240 AC 19 mp 210.9-211.5° C.; NMR δ_(H)(400MHz, DMSO) 5.42(2H, s), 6.61(2H, s), 6.72-6.78(1H, m), 6.99-7.03(2H, m), 7.71(1H, d, J 3.5Hz), 7.95(1H, t, J 1.0Hz) and 8.19(1H, s); Anal. Calcd for C₁₄H₁₀ClN₅OS: C, 50.68; H, 3.04; N, 21.10. Found: C, 50.57; H, 3.15; N, 21.11. M/Z 332(M+H)⁺. 241 Z 35 mp 246.2-248.0° C.; IR ν_(max)(Nujol)/cm⁻¹ 3410, 3325, 2924, 1689, 1463, 1377, 1289, 654 and 620; NMR δ_(H)(400MHz, DMSO) 2.49(3H, s), 7.76(1H, br s), 8.02(1H, d, J 8.5Hz), 8.76(1H, s), 8.81(1H, d, J 7.5Hz) and 8.87(1H, s); Retention time(20/50): 1.89min 242 AF 42 IR ν_(max)(Nujol)/cm⁻¹ 4330, 4259, 3239, 1716, 1665, 1597, 1518, 1464, 1404 and 1378; NMR δ_(H)(400MHz, DMSO) 1.11(3H, s), 1.12(3H, s), 1.15(3H, s), 1.16(3H, s), 5.36(2H, s), 6.79-6.83(1H, m), 7.16-7.22(1H, m), 7.22-7.26(1H, m), 7.30(2H, d, J 3.5Hz), 7.36-7.40(1H, m), 7.84(1H, d, J 3.0Hz), 8.05(1H, s), 8.56(1H, s), 9.71(1H, s), 10.71(1H, s). 243 AC 33 Mp 299.8° C.; IR ν_(max)(Nujol)/cm⁻¹ 3470, 3356, 2922, 2854, 1621, 1607, 1592, 1567, 1492, 1462 and 1377; NMR δ_(H)(400MHz, DMSO) 9.20-7.85(3H, br m), 7.46-7.36(1H, m), 7.33-7.16(3H, m), 7.11(2H, br s), 5.48(2H, s) and 2.45(3H, s). 244 AJ 12 mp 259.2° C.; NMR δ_(H)(400MHz, DMSO) 3.29(3H, s), 5.40(2H, s), 6.69(2H, br s), 7.06-7.20(2H, m), 7.21-7.31(1H, m), 7.33-7.42(1H, m), 7.56(1H, s) and 8.23(1H, s); Retention time(80:50): 2.15min 245 AK 46 IR ν_(max)(Nujol)/cm⁻¹ 3643, 3464, 3263, 3099, 1636, 1601, 1567, 1413, 1311, 1221 and 1170; NMR δ_(H)(400MHz, DMSO) 4.17(2H, br s), 4.76(2H, s), 6.52(2H, br s), 6.74(1H, dd, J 1.5, 3.5Hz), 7.15-7.24(5H, m), 7.72(1H, dd, J 1.0, 3.5Hz), 7.94(1H, dd, J 1.0, 1.5Hz) and 8.08(1H, s); Retention time: 0.70min. 246 Q 42 IR ν_(max)(Nujol)/cm⁻¹ 3486, 3281, 3182, 3075, 1657, 1605, 1563, 1460, 1409 and 1377; NMR δ_(H)(400MHz, DMSO) 0.85(3H, t, J 7.5Hz), 1.05(3H, d, J 6.5Hz), 1.37-1.46(2H, m), 3.63-3.72(1H, m), 4.74(2H, s), 6.48(2H, s), 6.75(1H, s), 7.72(1H, d, J 2.5Hz), 7.95(1H, s) and 8.02-8.09(2H, m). 247 Q 13 NMR δ_(H)(400MHz, DMSO) 1.05(3H, t, J 7.0Hz), 3.07-3.16(2H, m), 4.74(2H, s), 6.50(2H, s), 6.74-6.76(1H, m), 7.72(1H, dd, J 3.5Hz, 1.0Hz), 7.94-7.95(1H, m), 8.04(1H, s) and 8.20(1H, t, J 5.0Hz); Anal. calcd for C₁₃H₁₄N₆O₂. 0.35 H₂O: C, 53.36; H, 5.06; N, 28.72. Found: C, 53.39; H, 5.03; N, 28.38. 248 Q 42 NMR δ_(H)(400MHz, DMSO) 3.70-3.77(2H, m), 4.80(2H, s), 5.10(1H, d, J 9.5Hz), 5.21(1H, d, J 17.0Hz), 5.75-5.88(1H, m), 6.50(2H, s), 6.75(1H, s), 7.72(1H, d, J 2.5Hz), 7.95(1H, s), 8.05(1H, s) and 8.39(1H, t, J 5.0Hz); Anal. calcd for C₁₄H₁₄N₆O₂.0.7 H₂O: C, 54.08; H, 4.99; N, 27.03. Found: C, 53.96; H, 4.64; N, 26.78. 249 Q 43 NMR δ_(H)(400MHz, DMSO) 5.01(2H, s), 6.54(2H, s), 6.76(1H, s), 7.27-7.33(1H, m), 7.36-7.45(1H, m), 7.70-7.77(2H, m), 7.96(1H, s), 8.10(1H, s) and 10.66(1H, s); Anal. calcd for C₁₇H₁₂N₆O₂F₂.1.8 H₂O: C, 50.70; H, 3.90; N, 20.87. Found: C, 50.87; H, 3.75; N, 20.58. 250 AF 54 IR ν_(max)(Nujol)/cm⁻¹ 3552, 3397, 3336, 3224, 1644, 1589, 1567, 1464, 1409, 1377, 1331 and 1300; NMR δ_(H)(400MHz, DMSO) 2.15(3H, s), 2.35(3H, s), 5.28(2H, s), 6.74-6.77(1H, m), 6.92(1H, s), 6.97(1H, d, J 8.0Hz), 7.04(1H, d, J 7.5Hz), 7.28(1H, t, J 8.0Hz) 7.74(1H, d, J 3.0Hz), 7.96(1H, s), 8.14(1H, s) and 10.46(1H, s). 251 AL 45 mp 247-252° C.; IR ν_(max)(Nujol)/cm⁻¹ 3328, 2922, 1661, 1586, 1464, 1378 and 767; NMR δ_(H)(400MHz, DMSO) 1.28(3H, d, J 6.5Hz), 3.74-3.87(1H, m), 4.30(1H, dd, J 14, 5.5Hz), 4.43(1H, dd, J 14, 7.5Hz), 6.91-6.95(1H, m), 7.99(1H, d, J 3.5Hz), 8.23(1H, s) and 8.46-8.60(4H, m); Retention time(50:20): 0.81min 252 Q 44 IR ν_(max)(Nujol)/cm⁻¹ 3480, 3275, 3189, 3086, 1660, 1608, 1568, 1462, 1414, 1378 and 1359; NMR δ_(H)(400MHz, DMSO) 2.20(6H, s), 2.37(2H, t, J 6.0Hz), 3.21(2H, q, J 6.0Hz), 4.76(2H, s), 6.50(2H, s), 6.73-6.77(1H, m), 7.72(1H, d, J 3.0Hz), 7.95(1H, s), 8.04(1H, s), 8.19(1H, t, J 5.0Hz); Anal. calcd for C₁₅H₁₉N₇O₂.0.6 H₂O: C, 52.96; H, 5.99; N, 28.82. Found: C, 52.84; H, 5.83; N, 28.58. 253 AC 42 IR ν_(max)(Nujol)/cm⁻¹ 2923, 1651, 1463; NMR δ_(H)(400MHz, DMSO) 8.37(1H, s), 8.07-8.06(1H, m), 7.81-7.79(1H, m), 7.40-7.35(2H, m), 7.21-7.16(2H, m), 6.83-6.81(1H, m) and 5.32(2H, s). 254 AL 37 IR ν_(max)(Nujol)/cm⁻¹ 3500-2500 br, 2923, 2853, 1659, 1585, 1463 and 1378; NMR δ_(H)(400MHz, DMSO) 8.52(1H, s), 8.48(2H, br s), 8.21(1H, s), 7.96(1H, d, J 3.5Hz), 6.91(1H, d, J 3.5Hz), 4.42(1H, dd, J 14.5, 7.5Hz), 4.29(1H, dd, J 14.5, 5.5Hz), 3.88-3.73(1H, m) and 2.33(2H, s). 255 X 32 Mp 181.6-181.7° C.; NMR δ_(H)(400MHz, DMSO) 7.98-7.95(1H, m), 7.95-7.93(1H, m), 7.71(1H, d, J 3.5Hz), 7.00-6.94(1H, br m), 6.74(1H, dd, J 3.5, 2.0Hz), 6.49(2H, br s), 4.10(2H, br t, J 5.5Hz), 3.34(2H, br q, J 6.0Hz) and 1.33(9H, s). 256 AC 12 IR ν_(max)(Nujol)/cm⁻¹ 3318, 2922, 2854, 1604, 1588, 1538, 1456, 1406, 1377, 1356 and 1308; NMR δ_(H)(400MHz, DMSO) 8.20(1H, s), 7.97-7.94(1H, m), 7.70(1H, d, J 3.5Hz), 7.25(2H, d, J 8.0Hz), 7.18(2H, d, J 8.0Hz), 7.06(4H, d, J 8.0Hz), 6.76-6.71(1H, m), 5.21(2H, s), 4.50(2H, br d, J 6.0Hz), 2.26(3H, s) and 2.25(3H, s). 257 F 99 Mp 190° C. (dec); IR ν_(max)(Nujol)/cm⁻¹ 3379, 2923, 2854, 1679, 1649, 1626, 1600, 1585, 1462 and 1377; NMR δ_(H)(400MHz, DMSO) 8.49(1H, s), 8.39-8.25(3H, m), 8.19(1H, s), 7.93(1H, d, J 3.5Hz), 6.90(1H, dd, J 3.5, 1.5Hz), 4.42(2H, t, J 6.0Hz) and 3.41-3.31(2H, m). 258 AC 2 NMR δ_(H)(400MHz, DMSO) 7.74(1H, s), 7.71(1H, s), 7.57(1H, d, J 3.5Hz), 7.22(5H, d, J 7.5Hz), 7.15-7.01(7H, m), 6.57(1H, dd, J 3.5, 1.5Hz), 5.17(2H, s), 4.93(4H, br s), 2.33(6H, s) and 2.31(3H, s). 259 AC 29 IR ν_(max)(Nujol)/cm⁻¹ 3324, 3189, 3085, 1649, 1587, 1568, 1527, 1463, 1411, 1377 and 1347; NMR δ_(H)(400MHz, DMSO) 5.48(2H, s), 6.58(2H, s), 6.73-6.77(1H, m), 7.57(1H, t, J 9.5Hz), 7.72(1H, d, J 2.5Hz), 7.96(1H, s), 8.06-8.10(1H, m), 8.21(1H, s) and 8.26-8.31(1H, m). 260 AG 55 IR ν_(max)(Nujol)/cm⁻¹ 2924, 2854, 1587, 1516, 1462; NMR δ_(H)(400MHz, DMSO) 9.44(1H, s), 8.17(1H, s), 7.96-7.95(1H, m), 7.73-7.72(1H, m), 7.15(2H, d, J 8.5Hz), 6.76-6.74(1H, m), 6.72(2H, d, J 8.5Hz), 6.60(2H, br s) and 5.17(2H, s). 261 AC 70 IR ν_(max)(Nujol)/cm⁻¹ 3290, 2922, 2854, 1644, 1514, 1464; NMR δ_(H)(400MHz, DMSO) 8.17(1H, s), 7.95-7.94(1H, m), 7.72-7.70(1H, m), 7.26(2H, d, J 8.5Hz), 6.90(2H, d, J 8.5Hz), 6.75-6.73(1H, m), 6.54(2H, br s), 5.23(2H, s) and 3.72(3H, s). 262 AM 46 Mp 257-259° C.; IR ν_(max)(Nujol)/cm⁻¹ 3326, 3147, 3111, 1654, 1640, 1615, 1587, 1461, 1415 and 1376; NMR δ_(H)(400MHz, DMSO) 8.62(1H, s), 8.10(1H, d, J 2.0Hz), 7.48(1H, d, J 2.5Hz), 7.45-7.36(1H, m), 7.31-7.24(2H, m), 7.23-7.16(1H, m) and 5.43(1H, s). 263 AM 28 NMR δ_(H)(400MHz, DMSO) 5.65(2H, s), 7.18-7.31(2H, m), 7.36-7.45(1H, m), 7.55-7.62(1H, m), 8.64(1H, s), 8.87(1H, s) and 9.58(2H, s); Retention time: 0.98min (80:50) 264 AM 76 IR ν_(max)(Nujol)/cm⁻¹ 3500-2500 br, 2921, 1650, 1609, 1584, 1526, 1462, 1415 and 1377; NMR δ_(H)(400MHz, DMSO) 8.75(1H, s), 8.14(1H, d, J 2.0Hz), 7.51(1H, d, J 2.5Hz), 7.43(1H, t, J 8.0Hz), 7.29-7.20(3H, m) and 5.43(2H, s). 265 AO 7 IR ν_(max)(DR)/cm⁻¹ 3311, 2919, 1646, 1463, 1378, 999 and 738; NMR δ_(H)(400MHz, DMSO) 8.74(1H, s), 7.69-7.59(1H, m), 7.58-7.51(1H, m), 7.48(1H, t, J 7.5Hz), 7.34-7.24(4H, m), 5.42(2H, s) and 2.40(3H, s). 266 AC 26 NMR δ_(H)(400MHz, DMSO) 8.16(1H, s), 7.67(1H, d, J 3.5Hz), 7.25(1H, t, J 8.0Hz), 6.91-6.83(2H, m), 6.81(1H, d, J 7.5Hz), 6.54(2H, br s), 6.38(1H, d, J 3.5Hz), 5.26(2H, s), 3.72(3H, s) and 2.40(3H, s). 267 AC 38 mp 190.5-190.6° C.; IR ν_(max)(DR)/cm⁻¹ 3502, 3306, 3192, 3089, 2710, 1766, 1633 and 1228; NMR δ_(H)(400MHz, DMSO) 9.29(1H, s), 9.12(1H, s), 8.24(1H, s), 7.43-7.33(1H, m), 7.28-7.21(1H, m), 7.20-7.10(2H, m), 6.61(2H, br s) and 5.40(2H, s). 268 AC 37 mp 183.0-183.1° C.; IR ν_(max)(DR)/cm⁻¹ 3328, 3209, 3091, 2855, 1598, 1519, 1466; NMR δ_(H)(400MHz, DMSO) 8.21(1H, s), 7.96-7.95(1H, m), 7.80-7.76(1H, m), 7.75-7.74(1H, m), 7.35(1H, d, J 7.5Hz), 7.00(1H, d, J 7.5Hz), 6.76-6.75(1H, m), 6.53(2H, br s), 5.97-5.87(1H, m), 5.41(2H, s), 5.31-5.25(1H, m), 5.18-5.14(1H, m), 4.50(2H, s) and 4.05-4.03(2H, m); Anal. Calcd for C₁₉H₁₈N₆O₂.0.1 H₂O: C, 62.66; H, 5.04; N, 23.08. Found: C, 62.45; H, 4.98; N, 22.91. 269 AC 75 IR ν_(max)(Nujol)/cm⁻¹ 3332, 3204, 2923, 1648, 1588, 1515, 1464, 1342, 1166, 1010, 842 and 738; NMR δ_(H)(400MHz, DMSO) 5.40(2H, s), 6.57(2H, s), 6.75-6.76(1H, m), 7.26(1H, dd, J 8.5, 1.5Hz), 7.38-7.41(1H, m), 7.74(1H, d, J 3.5Hz), 7.94-7.98(2H, m) and 8.24(1H, s); Anal. calcd for C₁₇H₁₄N₆O₃.0.5 H₂O: C, 56.82; H, 4.21; N, 23.39. Found: C, 57.07; H, 4.13; N, 22.99. 270 AC 29 mp 190.4-190.5° C.; IR ν_(max)(Nujol)/cm⁻¹ 3457, 3311, 2923, 1724, 1586, 1456, 1348, 1129, 849, 757, 523 and 516; NMR δ_(H)(400MHz, DMSO) 8.15(1H, s), 8.02(1H, d, J 8.5Hz), 7.97-7.94(1H, m), 7.72(2H, t, J 3.5Hz), 7.29(1H, t, J 7.5Hz), 7.04(1H, d, J 7.0Hz), 6.95(1H, d, J 4.0Hz), 6.75-6.72(1H, m), 6.57(2H, s), 5.56(2H, s) and 1.64(9H, s). 271 AQ 69 mp 305.4-306.8° C.; IR ν_(max)(Nujol)/cm⁻¹ 3324, 3209, 2923, 1639, 1592, 1465, 1411, 1303, 1166, 1015, 851 and 750; NMR δ_(H)(400MHz, DMSO) 11.21(1H, s), 8.10(1H, s), 7.96-7.94(1H, m), 7.71(1H, d, J 4.0Hz), 7.35(2H, t, J 3.0Hz), 7.03(1H, t, 7.5Hz), 6.78(1H, d, J 8.0Hz), 6.75-6.72(1H, m), 6.56(3H, s) and 5.53(2H, s). 272 AQ 62 IR ν_(max)(DR)/cm⁻¹ 3482, 3201, 1595, 1461, 1208, 1141, 1100, 1023, 949, 887, 840, 793, 738, 655, 595 and 505; NMR δ_(H)(400MHz, DMSO) 11.08(1H, s), 8.17(1H, s), 7.95-7.93(1H, m), 7.71(1H, d, J 4.0Hz), 7.48(1H, s), 7.35-7.32(2H, m), 7.09(1H, d, J 8.0Hz), 6.75-6.73(1H, m), 6.54(2H, s), 6.39(1H, s) and 5.34(2H, s). 273 AC 82 NMR δ_(H)(400MHz, DMSO) 8.29(1H, s), 8.07(1H, s), 7.81(1H, d, J 8.5Hz), 7.57(2H, d, J 4.0Hz), 7.51(1H, d, J 3.5Hz), 7.39(1H, s), 6.79-6.76(1H, m), 6.66(1H, s), 6.52(1H, s), 6.44(1H, d, J 3.5Hz), 5.50(2H, s) and 1.59(9H, d, J 7.5Hz). Adenosine Receptor Binding Binding Affinities at hA_(2A) Receptors

The compounds were examined in an assay measuring in vitro binding to human adenosine A_(2A) receptors by determining the displacement of the adenosine A_(2A) receptor selective radioligand [³H]-CGS 21680 using standard techniques. The results are summarised in Table 3. TABLE 3 Example K_(i) (nM) Example 3 23 Example 13 12 Example 26 1 Example 36 7 Example 37 4 Example 38 1 Example 39 1 Example 45 2 Example 47 1 Example 52 5 Example 57 12 Example 68 9 Example 79 1 Example 80 5 Example 83 13 Example 92 6 Example 93 4 Example 106 1 Example 112 8 Example 118 3 Example 125 6 Example 126 7 Example 127 9 Example 141 36 Example 157 4 Example 159 10 Example 162 8 Example 185 7 Example 189 21 Example 192 24 Example 198 7 Example 201 2 Example 202 1 Example 208 6 Example 211 3 Example 212 35 Example 235 4 Example 240 7 Example 244 7 Example 259 11 Evaluation of Potential Anti-Parkinsonian Activity In Vivo Haloperidol-Induced Hypolocomotion Model

It has previously been demonstrated that adenosine antagonists, such as theophylline, can reverse the behavioural depressant effects of dopamine antagonists, such as haloperidol, in rodents (Mandhane S. N. et al., Adenosine A₂ receptors modulate haloperidol-induced catalepsy in rats. Eur. J. Pharmacol. 1997, 328, 135-141). This approach is also considered a valid method for screening drugs with potential antiparkinsonian effects. Thus, the ability of novel adenosine antagonists to block haloperidol-induced deficits in locomotor activity in mice can be used to assess both in vivo and potential antiparkinsonian efficacy.

Method

Female TO mice (25-30 g) obtained from TUCK, UK, are used for all experiments. Animals are housed in groups of 8 [cage size−40 (width)×40 (length)×20 (height)cm] under 12 hr light/dark cycle (lights on 08:00 hr), in a temperature (20±2° C.) and humidity (55±15%) controlled environment. Animals have free access to food and water, and are allowed at least 7 days to acclimatize after delivery before experimental use.

Drugs

Liquid injectable haloperidol (1 ml Serenance ampoules from Baker Norton, Harlow, Essex, each containing haloperidol BP 5 mg, batch # P424) are diluted to a final concentration of 0.02 mg/ml using saline. Test compounds are typically prepared as aqueous suspensions in 8% Tween. All compounds are administered intraperitoneally in a volume of 10 ml/kg.

Procedure

1.5 hours before testing, mice are administered 0.2 mg/kg haloperidol, a dose that reduces baseline locomotor activity by at least 50%. Test substances are typically administered 5-60 minutes prior to testing. The animals are then placed individually into clean, clear polycarbonate cages [20 (width)×40 (length)×20 (height) cm, with a flat perforated, Perspex lid]. Horizontal locomotor activity is determined by placing the cages within a frame containing a 3×6 array of photocells linked to a computer, which tabulates beam breaks. Mice are left undisturbed to explore for 1 hour, and the number of beams breaks made during this period serves as a record of locomotor activity which is compared with data for control animals for statistically significant differences.

6-OHDA Model

Parkinson's disease is a progressive neurodegenerative disorder characterised by symptoms of muscle rigidity, tremor, paucity of movement (hypokinesia), and postural instability. It has been established for some time that the primary deficit in PD is a loss of dopaminergic neurones in the substantia nigra which project to the striatum, and indeed a substantial proportion of striatal dopamine is lost (ca 80-85%) before symptoms are observed. The loss of striatal dopamine results in abnormal activity of the basal ganglia, a series of nuclei which regulate smooth and well co-ordinated movement (Blandini F. et al., Glutamate and Parkinson's Disease. Mol. Neurobiol. 1996, 12, 73-94). The neurochemical deficits seen in Parkinson's disease can be reproduced by local injection of the dopaminergic neurotoxin 6-hydroxydopamine into brain regions containing either the cell bodies or axonal fibres of the nigrostriatal neurones.

By unilaterally lesioning the nigrostriatal pathway on only one-side of the brain, a behavioural asymmetry in movement inhibition is observed. Although unilaterally-lesioned animals are still mobile and capable of self maintenance, the remaining dopamine-sensitive neurones on the lesioned side become supersenstive to stimulation. This is demonstrated by the observation that following systemic administration of dopamine agonists, such as apomorphine, animals show a pronounced rotation in a direction contralateral to the side of lesioning. The ability of compounds to induce contralateral rotations in 6-OHDA lesioned rats has proven to be a sensitive model to predict drug efficacy in the treatment of Parkinson's Disease.

Animals

Male Sprague-Dawley rats, obtained from Charles River, are used for all experiments. Animals are housed in groups of 5 under 12 hr light/dark cycle (lights on 08:00 hr), in a temperature (20±2° C.) and humidity (55±15%) controlled environment. Animals have free access to food and water, and are allowed at least 7 days to acclimatize after delivery before experimental use.

Drugs

Ascorbic acid, desipramine, 6-OHDA and apomorphine (Sigma-Aldrich, Poole, UK). 6-OHDA is freshly prepared as a solution in 0.2% ascorbate at a concentration of 4 mg/mL prior to surgery. Desipramine is dissolved in warm saline, and administered in a volume of 1 ml/kg. Apomorphine is dissolved in 0.02% ascorbate and administered in a volume of 2 mL/kg. Test compounds are suspended in 8% Tween and injected in a volume of 2 ml/kg.

Surgery

15 minutes prior to surgery, animals are given an intraperitoneal injection of the noradrenergic uptake inhibitor desipramine (25 mg/kg) to prevent damage to non-dopamine neurones. Animals are then placed in an anaesthetic chamber and anaesthetised using a mixture of oxygen and isoflurane. Once unconscious, the animals are transferred to a stereotaxic frame, where anaesthesia is maintained through a mask. The top of the animal's head is shaved and sterilised using an iodine solution. Once dry, a 2 cm long incision is made along the midline of the scalp and the skin retracted and clipped back to expose the skull. A small hole is then drilled through the skill above the injection site. In order to lesion the nigrostriatal pathway, the injection cannula is slowly lowered to position above the right medial forebrain bundle at −3.2 mm anterior posterior, −1.5 mm medial lateral from bregma, and to a depth of 7.2 mm below the duramater. 2 minutes after lowing the cannula, 2 μL of 6-OHDA is infused at a rate of 0.5 μL/min over 4 minutes, yeilding a final dose of 8 μg. The cannula is then left in place for a further 5 minutes to facilitate diffusion before being slowly withdrawn. The skin is then sutured shut using Ethicon W501 Mersilk, and the animal removed from the strereotaxic frame and returned to its homecage. The rats are allowed 2 weeks to recover from surgery before behavioural testing.

Apparatus

Rotational behaviour is measured using an eight station rotameter system provided by Med Associates, San Diego, USA. Each station is comprised of a stainless steel bowl (45 cm diameter×15 cm high) enclosed in a transparent Plexiglas cover running around the edge of the bowl, and extending to a height of 29 cm. To assess rotation, rats are placed in cloth jacket attached to a spring tether connected to optical rotameter positioned above the bowl, which assesses movement to the left or right either as partial (45°) or full (360°) rotations. All eight stations are interfaced to a computer that tabulated data.

Procedure

To reduce stress during drug testing, rats are initially habituated to the apparatus for 15 minutes on four consecutive days. On the test day, rats are given an intraperitoneal injection of test compound 30 minutes prior to testing. Immediately prior to testing, animals are given a subcutaneous injection of a subthreshold dose of apomorphine, then placed in the harness and the number of rotations recorded for one hour. The total number of full contralatral rotations during the hour test period serves as an index of antiparkinsonian drug efficacy. 

1. A method of treating a disorder selected from a group consisting of: (i) movement disorders; (ii) acute and chronic pain; (iii) affective disorders; (iv) central and peripheral nervous system degenerative disorders; (v) schizophrenia and related psychoses; (vi) cognitive disorders; (vii) attention disorders; (viii) central nervous system injury; (ix) cerebral ischaemia; (x) myocardial ischaemia; (xi) muscle ischaemia; (xii) sleep disorders; (xiii) eye disorders selected from retinal ischaemia-reperfusion injury and diabetic neuropathy; (xiv) cardiovascular disorders; and (xv) diabetes and its complications; the method comprising administering to a subject in need of such treatment an effective dose of a compound of formula (I):

wherein R₁ is selected from the group consisting of alkyl, aryl, alkoxy, aryloxy, thioalkyl, thioaryl, CN, halo, NR₅R₆, NR₄COR₅, NR₄CONR₅R₆, NR₄CO₂R₇, and NR₄SO₂R₇; R₂ is selected from the group consisting of N, O, or S-containing heteroaryl groups, wherein the heteroaryl group is attached via an unsaturated ring carbon atom of said heteroaryl group which is adjacent to one or two N, O, or S-heteroatom(s), other than heteroaryl groups substituted at both positions adjacent the point of attachment of the heteroaryl group to the purine moiety; R₃ is selected from the group consisting of H, alkyl, COR₈, CONR₉R₁₀, CONR₈NR₉R₁₀, CO₂R₁₁, and SO₂R₁₁; R₄, R₅, and R₆ are independently selected from the group consisting of H, alkyl, and aryl, or where R₅ and R₆ are in an (NR₅R₆) group then R₅ and R₆ may be linked to form a heterocyclic ring; R₇ is alkyl or aryl; R₈, R₉, and R₁₀ are independently selected from the group consisting of H, alkyl, and aryl, or R₉ and R₁₀ may be linked to form a heterocyclic ring, or where R₈, R₉, and R₁₀ are in a (CONR₈NR₉R₁₀) group, R₈ and R₉ may be linked to form a heterocyclic group; and R₁₁ is alkyl or aryl, or a pharmaceutically acceptable salt thereof.
 2. The method of claim 1, wherein said disorder is a movement disorder.
 3. The method of claim 2, wherein the movement disorder is Parkinson's disease.
 4. The method of claim 3 for treatment of drug-induced Parkinsonism, post-encephalitic Parkinsonism, Parkinsonism induced by poisoning, or post-traumatic Parkinson's disease.
 5. The method of claim 2, wherein the movement disorder is selected from the group consisting of progressive supernuclear palsy, Huntingtons disease, multiple system atrophy, corticobasal degeneration, Wilsons disease, Hallerrorden-Spatz disease, progressive pallidal atrophy, Dopa-responsive dystonia-Parkinsonism, spasticity, and other disorders of the basal ganglia which result in dyskinesias.
 6. The method of claim 1, wherein the compound of formula (I) is administered in combination with one or more additional drugs useful in the treatment of movement disorders.
 7. The method of claim 6, wherein the components are in the same formulation.
 8. The method of claim 6, wherein the components are in separate formulations for administration simultaneously or sequentially.
 9. The method of claim 6, wherein said one or more additional drugs useful in the treatment of movement disorders are drugs useful in the treatment of Parkinson's disease.
 10. The method of claim 6, wherein the one or more additional drugs is L-DOPA or a dopamine agonist.
 11. The method of claim 1, wherein said disorder is selected from the group consisting of depression, cognitive impairment, memory impairment, acute pain, chronic pain, ADHD, and narcolepsy.
 12. The method of claim 11, wherein said cognitive or memory impairment disorder is Alzheimer's disease.
 13. The method of claim 1, wherein the subject is human.
 14. The method of claim 1, wherein the compound of formula (I) is selected from the group consisting of: N,N-Dimethyl-6-(2-furyl)-1H-purine-2-amine; 6-(2-Furyl)-1H-purine-2-amine; 6-(2-Furyl)-2-methylthio-1H-purine; 2-Amino-N-benzyl-6-(2-furyl)-9H-purine-9-carboxamide; 2-Amino-N-n-butyl-6-(2-furyl)-9H-purine-9-carboxamide; 2-Amino-6-(2-furyl)-N-(4-methoxybenzyl)-9H-purine-9-carboxamide; 2-Amino-6-(2-furyl)-N-(4-methylbenzyl)-9H-purine-9-carboxamide; 2-Amino-N-(2-chlorobenzyl)-6-(2-furyl)-9H-purine-9-carboxamide; (1S)-2-Amino-6-(2-furyl)-N-(1-phenylethyl)-9H-purine-9-carboxamide; 2-Amino-6-(2-furyl)-N-(3-methylbenzyl)-9H-purine-9-carboxamide; 2-Amino-6-(2-furyl)-N-n-pentyl-9H-purine-9-carboxamide; 6-(2-Furyl)-9-(1-phenyl-1-propene-3-yl)-9H-purine-2-amine; 6-(2-Furyl)-9-(3-phenylpropyl)-9H-purine-2-amine; 2-Amino-N-(4-fluorobenzyl)-6-(2-furyl)-9H-purine-9-carboxamide; 2-Amino-N-(3,4-dichlorobenzyl)-6-(2-furyl)-9H-purine-9-carboxamide; 6-(2-Furyl)-9-(4-isopropylbenzyl)-9H-purine-2-amine; 2-Amino-6-(2-furyl)-N-(2-phenylethyl)-9H-purine-9-carboxamide; 2-Amino-N-(2,4-dichlorobenzyl)-6-(2-furyl)-9H-purine-9-carboxamide; Benzyl 2-amino-6-(2-furyl)-9H-purine-9-carboxylate; N-Benzyl-2-methoxy-6-(2-furyl)-9H-purine-9-carboxamide; 2-Amino-N-benzyl-6-(2-furyl)-N-methyl-9H-purine-9-carboxamide; 9-(3-Chlorobenzyl)-6-(2-furyl)-9H-purine-2-amine; 6-(2-Furyl)-9-(3-methylbenzyl)-9H-purine-2-amine; 6-(2-Furyl)-9-(4-methylbenzyl)-9H-purine-2-amine; 2-Amino-N-(3-chlorophenyl)-6-(2-furyl)-9H-purine-9-acetamide; 9-(2-Fluorobenzyl)-6-(2-furyl)-9H-purine-2-amine; 6-(2-Furyl)-9-(4-trifluoromethylbenzyl)-9H-purine-2-amine; 9-(4-Bromophenyl)sulphonyl-6-(2-furyl)-9H-purine-2-amine; 6-(2-Furyl)-9-(2-phenylethenyl)sulphonyl-9H-purine-2-amine; 6-(2-Furyl)-9-(3-(3-pyridyl)propyl)-9H-purine-2-amine; 9-(3-Aminobenzyl)-6-(2-furyl)-9H-purine-2-amine; 6-(2-Furyl)-9-(3-methoxybenzyl)-9H-purine-2-amine; 2-Amino-6-(2-furyl)-N-(2-furylmethyl)-9H-purine-9-carboxamide; 2-Amino-6-(2-furyl)-N-(2-thienylmethyl)-9H-purine-9-carboxamide; 9-(4-Methylbenzyl)-6-(5-methyl-2-furyl)-9H-purine-2-amine; 9-(2,6-Difluorobenzyl)-6-(2-furyl)-9H-purine-2-amine; 6-(2-Furyl)-9-(6-methyl-2-pyridyl)methyl-9H-purine-2-amine; 6-(2-Furyl)-9-(2-(1-methyl-1H-imidazol-4-ylsulphonylamino)benzyl)-9H-purine-2-amine; 9-(5-Chloro-2-thienylmethyl)-6-(2-furyl)-9H-purine-2-amine; 9-(2-Fluorobenzyl)-6-(4-methyl-2-thiazolyl)-9H-purine-2-amine; and 9-(2-Fluoro-5-nitrobenzyl)-6-(2-furyl)-9H-purine-2-amine.
 15. A method of neuroprotection comprising administering to a subject in need of such treatment an effective dose of a compound of formula (I):

wherein R₁ is selected from the group consisting of alkyl, aryl, alkoxy, aryloxy, thioalkyl, thioaryl, CN, halo, NR₅R₆, NR₄COR₅, NR₄CONR₅R₆, NR₄CO₂R₇, and NR₄SO₂R₇; R₂ is selected from the group consisting of N, O, or S-containing heteroaryl groups, wherein the heteroaryl group is attached via an unsaturated ring carbon atom of said heteroaryl group which is adjacent to one or two N, O, or S-heteroatom(s), other than heteroaryl groups substituted at both positions adjacent the point of attachment of the heteroaryl group to the purine moiety; R₃ is selected from the group consisting of H, alkyl, COR₈, CONR₉R₁₀, CONR₈NR₉R₁₀, CO₂R₁₁, and SO₂R₁₁; R₄, R₅, and R₆ are independently selected from the group consisting of H, alkyl, and aryl, or where R₅ and R₆ are in an (NR₅R₆) group then R₅ and R₆ may be linked to form a heterocyclic ring; R₇ is alkyl or aryl; R₈, R₉, and R₁₀ are independently selected from the group consisting of H, alkyl, and aryl, or R₉ and R₁₀ may be linked to form a heterocyclic ring, or where R₈, R₉, and R₁₀ are in a (CONR₈NR₉R₁₀) group, R₈ and R₉ may be linked to form a heterocyclic group; and R₁₁ is alkyl or aryl, or a pharmaceutically acceptable salt thereof.
 16. The method of claim 15, wherein said method is for neuroprotection in a subject suffering from or at risk from a neurodegenerative disorder.
 17. The method of claim 16, wherein said neurodegenerative disorder is a movement disorder.
 18. The method of claim 17, wherein said movement disorder is selected from the group consisting of Parkinson's disease, drug-induced Parkinsonism, post-encephalitic Parkinsonism, Parkinsonism induced by poisoning, post traumatic Parkinson's disease, progressive supernuclear palsy, Huntingtons disease, multiple system atrophy, corticobasal degeneration, Wilsons disease, Hallerrorden-Spatz disease, progressive pallidal atrophy, Dopa-responsive dystonia-Parkinsonism, spasticity, and other disorders of the basal ganglia which result in dyskinesias.
 19. The method of claim 15, wherein the subject is human.
 20. A method of treating a disorder in which the blocking of adenosine A_(2A) receptors is beneficial selected from the group consisting of: (i) movement disorders; (ii) acute and chronic pain; (iii) affective disorders; (iv) central and peripheral nervous system degenerative disorders; (v) schizophrenia and related psychoses; (vi) cognitive disorders; (vii) attention disorders; (viii) central nervous system injury; (ix) cerebral ischaemia; (x) myocardial ischaemia; (xi) muscle ischaemia; (xii) sleep disorders; (xiii) eye disorders selected from retinal ischaemia-reperfusion injury and diabetic neuropathy; (xiv) cardiovascular disorders; and (xv) diabetes and its complications; the method comprising administering to a subject in need of such treatment an effective dose of a compound of formula (I):

wherein R₁ is selected from the group consisting of alkyl, aryl, alkoxy, aryloxy, thioalkyl, thioaryl, CN, halo, NR₅R₆, NR₄COR₅, NR₄CONR₅R₆, NR₄CO₂R₇, and NR₄SO₂R₇; R₂ is selected from the group consisting of N, O, or S-containing heteroaryl groups, wherein the heteroaryl group is attached via an unsaturated ring carbon atom of said heteroaryl group which is adjacent to one or two N, O, or S-heteroatom(s), other than heteroaryl groups substituted at both positions adjacent the point of attachment of the heteroaryl group to the purine moiety; R₃ is selected from the group consisting of H, alkyl, COR₈, CONR₉R₁₀, CONR₈NR₉R₁₀, CO₂R₁₁, and SO₂R₁; R₄, R₅, and R₆ are independently selected from the group consisting of H, alkyl, and aryl, or where R₅ and R₆ are in an (NR₅R₆) group then R₅ and R₆ may be linked to form a heterocyclic ring; R₇ is alkyl or aryl; R₈, R₉, and R₁₀ are independently selected from the group consisting of H, alkyl, and aryl, or R₉ and R₁₀ may be linked to form a heterocyclic ring, or where R₈, R₉, and R₁₀ are in a (CONR₈NR₉R₁₀) group, R₈ and R₉ may be linked to form a heterocyclic group; and R₁₁ is alkyl or aryl, or a pharmaceutically acceptable salt thereof.
 21. The method of claim 20, wherein the disorder is caused by hyperfunctioning of the adenosine receptors. 